Clinical Trials For Medical Devices And Drugs Relating To COVID-19 ...

Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations: SOR/2022-18

Canada Gazette, Part II, Volume 156, Number 5

Registration SOR/2022-18 February 11, 2022

FOOD AND DRUGS ACT PATENT ACT

P.C. 2022-100 February 10, 2022

Her Excellency the Governor General in Council, on the recommendation of the Minister of Health with respect to the provisions of the annexed Regulations other than sections 53 and 54, and on the recommendation of the Minister of Health and the Minister of Industry with respect to those sections 53 and 54, makes the annexed Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations pursuant to

• (a) section 30footnote a of the Food and Drugs Actfootnote b; and
• (b) subsection 134(1)footnote c of the Patent Actfootnote d.

Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations

Interpretation

Definitions

1 The following definitions apply in these Regulations.

Act means the Food and Drugs Act. (Loi) COVID-19 means the coronavirus disease 2019. (COVID-19) COVID-19 drug means a drug for human use that is manufactured, sold or represented for use in relation to COVID-19. (drogue utilisée en lien avec la COVID-19) COVID-19 drug authorization means an authorization to do any of the following activities:

• (a) import or sell a COVID-19 drug that is to be tested in a clinical trial;
• (b) conduct a clinical trial in respect of such a drug. (autorisation relative à une drogue utilisée en lien avec la COVID-19)

COVID-19 medical device means a medical device that is manufactured, sold or represented for use in relation to COVID-19. (instrument médical utilisé en lien avec la COVID-19) COVID-19 medical device authorization means an authorization to do any of the following activities:

• (a) import or sell a COVID-19 medical device that is to be tested in a clinical trial;
• (b) conduct a clinical trial in respect of such a device. (autorisation relative à un instrument médical utilisé en lien avec la COVID-19)

incident means any incident that involves a COVID-19 medical device tested in a clinical trial and that

• (a) is related to a failure of the device or a deterioration in its quality or effectiveness or any inadequacy in its labelling or its directions for use; or
• (b) has led to the death or a serious deterioration in the state of health of a clinical trial subject, user or other person or could do so were it to recur. (incident)

qualified investigator means a person who is a member in good standing of a professional association of persons entitled under the laws of a province to provide health care under their licence in that province and who

• (a) conducts a clinical trial; or
• (b) in the case of a clinical trial conducted by a team, is the responsible leader of that team. (chercheur compétent)

research ethics board means a body that is not affiliated with an applicant for a COVID-19 medical device authorization or a COVID-19 drug authorization, or a holder of such an authorization, and whose principal mandate 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. (comité d’éthique de la recherche)

Words and expressions

2 (1) Unless the context requires otherwise, words and expressions used in these Regulations have the same meaning as in the Medical Devices Regulations and the Food and Drug Regulations, as applicable.

Definition of clinical trial

(2) However, clinical trial has the same meaning as in section 2 of the Act, except as otherwise provided.

Application

Application

3 (1) These Regulations apply to the importation and sale of a COVID-19 medical device, other than a Class I device, that is to be tested in a clinical trial, to the importation and sale of a COVID-19 drug, other than a drug that is described in Schedule C to the Act, that is to be tested in a clinical trial and to the conduct of a clinical trial in respect of such a device or drug.

Non-application — COVID-19 medical device

(2) The Medical Devices Regulations, other than sections 6 and 7 and Schedule 1, do not apply to the importation or sale of a COVID-19 medical device that is to be tested in a clinical trial or to the conduct of a clinical trial in respect of such a device if a COVID-19 medical device authorization has been issued for that device and the authorization has not been revoked in whole.

Non-application — COVID-19 drug

(3) The following regulations do not apply to the importation or sale of a COVID-19 drug that is to be tested in a clinical trial or to the conduct of a clinical trial in respect of such a drug if a COVID-19 drug authorization has been issued for that drug and the authorization has not been revoked in whole:

• (a) the Food and Drug Regulations, other than sections A.01.022 to A.01.024, A.01.026, A.01.041, A.01.042, A.01.050, A.01.067, A.01.068, C.01.015, C.01.036, C.01.037 to C.01.040, C.01.040.2, C.01.051, C.01.064 to C.01.067, C.01.070, C.01.131, C.01.133 to C.01.136 and C.01.435 and Divisions 2 and 4 of Part C; and
• (b) the Blood Regulations.

PART 1 COVID-19 Medical Devices

Application

4 (1) An application for a COVID-19 medical device authorization must be submitted to the Minister in the form and manner specified by the Minister.

Content

(2) The application must contain sufficient information and material to enable the Minister to determine whether to issue the authorization and must include the following:

• (a) the name and contact information of the applicant and, if applicable, the importer;
• (b) the name and class of the device;
• (c) a description of the device and of the materials used in its manufacture and packaging;
• (d) a description of the features of the device that permit it to be used for the medical conditions, purposes and uses for which it is manufactured, sold or represented, including its performance specifications if those specifications are necessary for proper use;
• (e) the identifier of the device, including the identifier of any medical device that is part of a system, test kit, medical device group, medical device family or medical device group family;
• (f) the name and contact information of the manufacturer as they appear on the device label;
• (g) the address where the device is manufactured, if the address is different from the one provided in the contact information under paragraph (f);
• (h) the diagnosis, treatment, mitigation or prevention for which the device is required;
• (i) a list of the countries other than Canada where the device has been sold, the total number of units sold in those countries and a summary of any reported problems with the device and of any recalls of the device in those countries;
• (j) the known information in relation to the quality, safety and effectiveness of the device;
• (k) the directions for use, unless directions are not required for the device to be used safely and effectively;
• (l) an attestation by the applicant that documented procedures are in place in respect of distribution records, complaint handling, incident reporting and recalls;
• (m) a copy of the label of the device;
• (n) the name of the qualified investigator and their qualifications, including their training and experience;
• (o) the name and contact information of the institution at which the clinical trial is proposed to be conducted;
• (p) the protocol of the proposed clinical trial, including the number of clinical trial subjects, the number of units of the device proposed to be used for the clinical trial, the hypothesis for and objective of the clinical trial, the period of time during which the clinical trial will be conducted and a copy of the informed consent form;
• (q) a written undertaking from the qualified investigator to
  • (i) conduct the clinical trial in accordance with the protocol provided by the applicant,
  • (ii) inform each clinical trial subject of any risks and benefits associated with the use of the device and obtain the subject’s informed consent for its use, and
  • (iii) not permit the device to be used by any other person except under the direction of the qualified investigator; and
• (r) in the case of a Class III or IV device, for each clinical trial site, the name and contact information of the research ethics board that approved the protocol and informed consent form referred to in paragraph (p), if known at the time of submitting the application.

Class II devices

(3) Despite subsection (2), if the application for the authorization is in respect of a COVID-19 medical device that is a Class II device, the information and material set out in paragraphs (2)(c), (h) to (j), (n) and (q) may be omitted from the application.

Issuance

5 The Minister must issue a COVID-19 medical device authorization if the following requirements are met:

• (a) the applicant has submitted to the Minister an application that meets the requirements set out in section 4;
• (b) the applicant has submitted to the Minister any additional information or material requested under subsection 10(1) in the time, form and manner specified under subsection 10(2); and
• (c) the Minister determines that
  • (i) the use of the device that is to be tested in the clinical trial will not unduly affect the health or safety of clinical trial subjects, users or other persons,
  • (ii) the clinical trial is not contrary to the best interests of clinical trial subjects, and
  • (iii) the objectives of the clinical trial are achievable.

Research ethics board approval

6 A holder of a COVID-19 medical device authorization must not import or sell a COVID-19 medical device for which the authorization has been issued or conduct a clinical trial in respect of such a device unless the holder has obtained, for each clinical trial site, the approval of a research ethics board in respect of the protocol and informed consent form referred to in paragraph 4(2)(p).

Terms and conditions

7 The Minister may, at any time, impose terms and conditions on a COVID-19 medical device authorization or amend those terms and conditions.

Prohibition

8 (1) Subject to subsection (2), if the substance of any of the information or material referred to in paragraphs 4(2)(a) to (d), (f), (h), (j), (k) and (p) and, if applicable, submitted under subsection 10(1) is significantly different from the substance of the information or material contained in the application for a COVID-19 medical device authorization,

• (a) the conduct of the clinical trial referred to in the authorization that is issued as a result of that application is no longer authorized for the purposes of section 3.1 of the Act; and
• (b) the holder of the authorization must not import or sell the COVID-19 medical device for which the authorization was issued.

Amendment

(2) Subsection (1) does not apply if

• (a) the holder of the COVID-19 medical device authorization has submitted to the Minister an application to amend the authorization;
• (b) the Minister determines that the requirements set out in subparagraphs 5(c)(i) to (iii) are met;
• (c) the holder has submitted to the Minister any additional information or material requested under subsection 10(1) in the time, form and manner specified under subsection 10(2); and
• (d) the Minister amends the authorization.

Suspension

9 (1) The Minister may suspend, in whole or in part, a COVID-19 medical device authorization by notice, giving reasons, if

• (a) the Minister determines that any of the requirements set out in subparagraphs 5(c)(i) to (iii) is no longer met;
• (b) the holder of the authorization has not submitted to the Minister any additional information or material requested under subsection 10(1) in the time, form and manner specified under subsection 10(2); or
• (c) the holder of the authorization has contravened these Regulations or any provisions of the Act relating to the device.

Reinstatement

(2) The Minister must reinstate a COVID-19 medical device authorization if the holder of the authorization submits to the Minister, in the time, form and manner specified by the Minister, information or material that demonstrates that the situation giving rise to the suspension did not exist or has been corrected.

Additional information and material

10 (1) The Minister may request that an applicant for a COVID-19 medical device authorization or a holder of such an authorization submit any additional information or material, including samples, that is necessary to enable the Minister to determine whether to issue, amend or suspend the authorization.

Time, form and manner

(2) The applicant or holder must submit the information or material in the time, form and manner specified by the Minister.

Discontinuance

11 If a holder of a COVID-19 medical device authorization discontinues, in whole or in part, the clinical trial for which the authorization has been issued, the holder must, without delay,

• (a) notify the Minister, in writing, of the discontinuance and the reasons for it;
• (b) inform all qualified investigators, in writing, of the discontinuance and the reasons for it and advise them, in writing, of any potential risks to the health of clinical trial subjects, users or other persons; and
• (c) in respect of each clinical trial site at which the trial is discontinued, stop the importation or sale of the device as of the date of the discontinuance and take all reasonable measures to ensure the recovery of all unused quantities of the device that have been sold.

Discretionary revocation

12 (1) The Minister may revoke, in whole or in part, a COVID-19 medical device authorization by notice, giving reasons, if the holder of the authorization has not submitted to the Minister, in the time, form and manner specified by the Minister, the information or material referred to in subsection 9(2).

Mandatory revocation

(2) The Minister must revoke, in whole or in part, the authorization if the Minister has received a notice of discontinuance referred to in paragraph 11(a).

Labelling

13 (1) A person must not import or sell a medical device for which a COVID-19 medical device authorization has been issued or conduct a clinical trial in respect of such a device unless the device has a label that sets out the following information:

• (a) the name of the device;
• (b) the name and contact information of the manufacturer;
• (c) the identifier of the device, including the identifier of any medical device that is part of a system, test kit, medical device group, medical device family or device group family;
• (d) in the case of a Class III or IV device, the control number;
• (e) if the contents are not readily apparent, an indication of what the package contains, expressed in terms appropriate to the device, such as the size, net weight, length, volume or number of units;
• (f) a statement indicating that the device is sterile, if the device is to be sold in a sterile condition;
• (g) the expiry date of the device, if applicable;
• (h) the medical conditions, purposes and uses for which the device is manufactured, sold or represented, including its performance specifications if those specifications are necessary for proper use;
• (i) the directions for use, unless directions are not required for the device to be used safely and effectively;
• (j) any special storage conditions applicable to the device;
• (k) a statement indicating that the device is an investigational device;
• (l) a statement indicating that the device is to be used by qualified investigators only; and
• (m) in the case of an in vitro diagnostic device, a statement indicating that the performance specifications of the device have not been established.

Presentation of information

(2) The information required by subsection (1) to be set out on the label must be in English and in French.

Incident reporting

14 A holder of a COVID-19 medical device authorization must, within 10 days after becoming aware of an incident inside or outside Canada involving a COVID-19 medical device for which the authorization has been issued, report the incident to the Minister and specify the nature of the incident and the circumstances surrounding it.

Records

15 (1) A holder of a COVID-19 medical device authorization must record, handle and store all information in respect of the clinical trial for which the authorization has been issued in a manner that allows for the complete and accurate reporting as well as the interpretation and verification of the information.

Content

(2) The holder of the authorization must maintain complete and accurate records, which include the information and material referred to in subsection 4(2), in respect of a COVID-19 medical device for which the authorization has been issued in order to establish that the clinical trial is conducted in accordance with these Regulations.

Retention period

(3) The holder of the authorization must retain all records for the period during which the authorization has not been revoked in whole.

Distribution records

16 (1) A holder of a COVID-19 medical device authorization must maintain a distribution record in respect of each device that is imported or sold under the authorization or tested in a clinical trial under the authorization.

Withdrawal

(2) The distribution record must contain sufficient information to permit complete and rapid withdrawal of the COVID-19 medical device for which the authorization has been issued.

Retention period

(3) The holder — or former holder, in the case of an authorization that has been revoked in whole — of the authorization must retain the distribution record for the longer of

• (a) the projected useful life of the device, and
• (b) two years after the date on which the holder took possession, care or control of the device in Canada.

Timely retrieval

(4) Distribution records must be maintained in a manner that will allow their timely retrieval.

Complaint handling

17 A holder of a COVID-19 medical device authorization must, in respect of a COVID-19 medical device for which the authorization has been issued, maintain records of the following:

• (a) any reported problems relating to the performance characteristics or safety of the device that are received by the holder after the device was first sold in Canada; and
• (b) all actions taken by the holder in response to those problems.

Documented procedures

18 A holder of a COVID-19 medical device authorization must, in respect of a COVID-19 medical device for which the authorization has been issued, establish and implement documented procedures that will enable the holder to carry out

• (a) an effective and timely investigation of the problems referred to in paragraph 17(a); and
• (b) an effective and timely recall of the device.

Information — recall

19 (1) A holder of a COVID-19 medical device authorization must, on or before recalling a COVID-19 medical device for which the authorization has been issued, provide the Minister with the following:

• (a) the name of the device and its identifier, including the identifier of any medical device that is part of a system, test kit, medical device group, medical device family or medical device group family;
• (b) the name and contact information of the manufacturer and, if applicable, the importer, as well as the name and contact information of the establishment where the device was manufactured, if different from that of the manufacturer;
• (c) the reason for the recall, the nature of the defectiveness or possible defectiveness and the date on and circumstances under which it was discovered;
• (d) an evaluation of the risk associated with the defectiveness or possible defectiveness;
• (e) the number of affected units of the device that were manufactured or sold in Canada or imported into Canada;
• (f) the period during which the affected units of the device were sold in Canada;
• (g) the name of each person to whom the affected device was sold and the number of units sold to each person;
• (h) a copy of any communication issued with respect to the recall;
• (i) the proposed strategy for conducting the recall, including the date for beginning the recall, information as to how and when the Minister will be informed of the progress of the recall and the proposed date for its completion;
• (j) the proposed action to prevent a recurrence of the problem; and
• (k) the name, title and telephone number of the representative of the holder of the authorization to contact for any information concerning the recall.

Information — after completion of recall

(2) The holder of the authorization must, as soon as feasible after the completion of the recall, prepare and submit to the Minister a report on

• (a) the results of the recall; and
• (b) the action taken to prevent a recurrence of the problem.

Submission on holder’s behalf

(3) Despite subsections (1) and (2), the holder of the authorization may permit the importer of the COVID-19 medical device to prepare and submit, on the holder’s behalf, the information and material required under those subsections if the importer has the same information and material.

Notice to Minister

(4) The holder of the authorization must notify the Minister, in writing, if the holder has permitted the importer to prepare and submit the information and material with respect to the recall on the holder’s behalf.

PART 2 COVID-19 Drugs

Application

20 (1) An application for a COVID-19 drug authorization must be signed and dated by the applicant’s senior medical or scientific officer in Canada and their senior executive officer and must be submitted to the Minister in the form and manner specified by the Minister.

Content

(2) The application must contain sufficient information and material to enable the Minister to determine whether to issue the authorization and must include the following:

• (a) the protocol of the proposed clinical trial;
• (b) 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;
• (c) a clinical trial attestation containing
  • (i) the title of the protocol and the clinical trial number,
  • (ii) the brand name, chemical name or code for the drug,
  • (iii) the therapeutic and pharmacological classifications of the drug,
  • (iv) the medicinal ingredients of the drug,
  • (v) the non-medicinal ingredients of the drug,
  • (vi) the dosage form of the drug,
  • (vii) the name and contact information of the applicant,
  • (viii) if the drug is to be imported, the name and contact information of the applicant’s representative in Canada who is responsible for the sale of the drug,
  • (ix) for each clinical trial site, the name and contact information of the qualified investigator, if known at the time of submitting the application,
  • (x) for each clinical trial site, the name and contact information of the research ethics board that approved the protocol referred to in paragraph (a) and the informed consent form containing the statement referred to in paragraph (b), if known at the time of submitting the application, and
  • (xi) a statement that
    • (A) the clinical trial will be conducted in accordance with good clinical practices and these Regulations, and
    • (B) all information and material contained in, or referenced by, the application is complete and accurate and is not false or misleading;
• (d) the name and contact information 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, if known at the time of submitting the application;
• (e) the physical, chemical and pharmaceutical properties of the drug;
• (f) the pharmacological aspects of the drug, including its metabolites in all animal species tested;
• (g) the pharmacokinetics of the drug and the drug metabolism, including the biological transformation of the drug in all animal species tested;
• (h) any toxicological effects of the drug in any animal species tested under a single dose study, a repeated dose study or a special study;
• (i) any results of carcinogenicity studies in any animal species tested in respect of the drug;
• (j) any results of clinical pharmacokinetic studies of the drug;
• (k) any of the following information that was obtained from previous clinical trials in humans in respect of the drug;
  • (i) safety,
  • (ii) pharmacodynamics,
  • (iii) efficacy, and
  • (iv) dose responses;
• (l) if the drug contains a human-sourced excipient, including any used in the placebo,
  • (i) in the case where the excipient has been assigned a drug identification number under subsection C.01.014.2(1) of the Food and Drug Regulations or, in the case of a new drug, has been issued a notice of compliance under subsection C.08.004(1) of those Regulations, a statement to that effect, or
  • (ii) in any other case, sufficient information to support the identity, purity, potency, stability and safety of the excipient;
• (m) if the drug has not been assigned a drug identification number under subsection C.01.014.2(1) of the Food and Drug Regulations or, in the case of a new drug, a notice of compliance has not been issued under section C.08.004 or C.08.004.01 of those Regulations, the chemistry and manufacturing information in respect of the drug, including its site of manufacture; and
• (n) the proposed date for the commencement of the clinical trial at each clinical trial site, if known at the time of submitting the application.

Marketed drug

(3) If the application for the authorization is in respect of a COVID-19 drug that meets the requirements of paragraphs 27(a) to (c), the application must also contain

• (a) a copy of the label of the drug; and
• (b) information demonstrating that the proposed use of the drug is consistent with the standard of medical practice.

Issuance

21 The Minister must issue a COVID-19 drug authorization if the following requirements are met:

• (a) the applicant has submitted to the Minister an application that meets the requirements set out in section 20;
• (b) the applicant has submitted to the Minister any additional information or material requested under subsection 30(1) in the time, form and manner specified under subsection 30(2); and
• (c) the Minister determines that
  • (i) the use of the drug that is to be tested in the clinical trial will not unduly affect the health or safety of clinical trial subjects or other persons,
  • (ii) the clinical trial is not contrary to the best interests of clinical trial subjects, and
  • (iii) the objectives of the clinical trial are achievable.

Additional information prior to clinical trial

22 A holder of a COVID-19 drug authorization must not import or sell a COVID-19 drug for which the authorization has been issued or conduct a clinical trial in respect of such a drug unless the holder has

• (a) for each clinical trial site, obtained the approval of a research ethics board in respect of the protocol referred to in paragraph 20(2)(a) and the informed consent form that contains the statement referred to in paragraph 20(2)(b); and
• (b) submitted to the Minister the information and material referred to in subparagraphs 20(2)(c)(ix) and (x) and paragraphs 20(2)(d) and (n), if it was not submitted at the time of submitting the application.

Terms and conditions

23 The Minister may, at any time, impose terms and conditions on a COVID-19 drug authorization or amend those terms and conditions.

Prohibition

24 (1) Subject to subsection (2), if the substance of any of the information or material referred to in paragraph 20(2)(a) or (m) is significantly different from the substance of the information or material contained in the application for a COVID-19 drug authorization,

• (a) the conduct of the clinical trial referred to in the authorization that is issued as a result of that application is no longer authorized for the purposes of section 3.1 of the Act; and
• (b) the holder of the authorization must not import or sell the COVID-19 drug for which the authorization was issued.

Amendment

(2) Subsection (1) does not apply if

• (a) the holder of the COVID-19 drug authorization has submitted to the Minister an application to amend the authorization;
• (b) for each clinical trial site, the holder has obtained the approval of a research ethics board in respect of the protocol referred to in paragraph 20(2)(a) and the informed consent form that contains the statement referred to in paragraph 20(2)(b);
• (c) the holder has submitted to the Minister the information and material referred to in subparagraphs 20(2)(c)(ix) and (x) and paragraphs 20(2)(d) and (n), if it was not submitted at the time of submitting the application;
• (d) the Minister determines that the requirements set out in subparagraphs 21(c)(i) to (iii) are met;
• (e) the holder has submitted to the Minister any additional information or material requested under subsection 30(1) in the time, form and manner specified under subsection 30(2); and
• (f) the Minister amends the authorization.

Immediate change

(3) Despite subsections (1) and (2), if an immediate change is required to be made to the substance of any of the information or material referred to in paragraph 20(2)(a) or (m) because the clinical trial or the use of the COVID-19 drug that is tested in the clinical trial endangers the health of a clinical trial subject or other person, the holder of the authorization may immediately make the change.

Immediate change — application to amend

(4) The holder of the authorization must, within 15 days after making the change referred to in subsection (3), submit the application referred to in subsection (2) to amend the authorization.

Prohibition — import

25 A holder of a COVID-19 drug authorization must not import a COVID-19 drug for which the authorization has been issued if the sale of the drug would constitute a violation of the Act.

Prohibition — import and sale

26 A holder of a COVID-19 drug authorization must not import or sell a COVID-19 drug for which the authorization has been issued unless the holder has a representative in Canada who is responsible for the sale of the drug.

Marketed drugs

27 Paragraphs 20(2)(e) to (l), section 33 and paragraphs 35(2)(a) to (c) do not apply to a COVID-19 drug for which a COVID-19 drug authorization has been issued if

• (a) the use of the drug is consistent with the standard of medical practice;
• (b) the drug has been issued a notice of compliance under subsection C.08.004(1) of the Food and Drug Regulations or has been assigned a drug identification number under subsection C.01.014.2(1) of those Regulations; and
• (c) the clinical trial for which the authorization has been issued is in respect of a purpose or condition of use other than that for which the notice of compliance was issued or drug identification number was assigned.

Good clinical practices

28 A holder of a COVID-19 drug authorization must ensure that the clinical trial for which the authorization has been issued is conducted in accordance with good clinical practices and, without limiting the generality of the foregoing, must ensure that

• (a) the clinical trial is scientifically sound and clearly described in the protocol;
• (b) the clinical trial is conducted, and the drug is used, in accordance with the protocol and these Regulations;
• (c) systems and procedures that assure the quality of every aspect of the clinical trial are implemented;
• (d) for each clinical trial site, the approval of a research ethics board is obtained before the clinical trial begins;
• (e) at each clinical trial site, there is no more than one qualified investigator;
• (f) at each clinical trial site, medical care and medical decisions, in respect of the clinical trial, are under the supervision of a health care professional who is authorized to provide medical care and make medical decisions;
• (g) each person who is involved in the conduct of the clinical trial is qualified by education, training and experience to perform their respective tasks;
• (h) informed consent, given in accordance with the applicable laws governing consent, is obtained from every person before they participate in the clinical trial, but only after that person has been informed of
  • (i) the risks and anticipated benefits to their health arising from participation in the clinical trial, and
  • (ii) all other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial; and
• (i) the drug is manufactured, handled and stored in accordance with the applicable good manufacturing practices referred to in Divisions 2 and 4 of Part C of the Food and Drug Regulations, with the exception of sections C.02.019, C.02.025 and C.02.026 of those Regulations.

Suspension

29 (1) The Minister may suspend, in whole or in part, a COVID-19 drug authorization by notice, giving reasons, if

• (a) the Minister determines that any of the requirements set out in subparagraphs 21(c)(i) to (iii) is no longer met;
• (b) the holder of the authorization has not submitted to the Minister any additional information or material requested under subsection 30(1) in the time, form and manner specified under subsection 30(2); or
• (c) the holder of the authorization has contravened these Regulations or any provisions of the Act relating to the drug.

Reinstatement

(2) The Minister must reinstate a COVID-19 drug authorization if the holder of the authorization submits to the Minister, in the time, form and manner specified by the Minister, information or material that demonstrates that the situation giving rise to the suspension did not exist or has been corrected.

Additional information and material

30 (1) The Minister may request that an applicant for a COVID-19 drug authorization or a holder of such an authorization submit any additional information or material, including samples, that is necessary to enable the Minister to determine whether to issue, amend or suspend the authorization.

Time, form and manner

(2) The applicant or holder must submit the information or material in the time, form and manner specified by the Minister.

Discontinuance

31 If a holder of a COVID-19 drug authorization discontinues, in whole or in part, the clinical trial for which the authorization has been issued, the holder must, without delay,

• (a) notify the Minister, in writing, of the discontinuance and the reasons for it;
• (b) inform all qualified investigators, in writing, of the discontinuance and the reasons for it and advise them, in writing, of any potential risks to the health of clinical trial subjects or other persons; and
• (c) in respect of each clinical trial site at which the trial is discontinued, stop the importation or sale of the drug as of the date of the discontinuance and take all reasonable measures to ensure the recovery of all unused quantities of the drug that have been sold.

Discretionary revocation

32 (1) The Minister may revoke, in whole or in part, a COVID-19 drug authorization by notice, giving reasons, if the holder of the authorization has not submitted to the Minister, in the time, form and manner specified by the Minister, the information or material referred to in subsection 29(2).

Mandatory revocation

(2) The Minister must revoke, in whole or in part, the authorization if the Minister has received a notice of discontinuance referred to in paragraph 31(a).

Labelling

33 (1) A person must not import or sell a COVID-19 drug for which a COVID-19 drug authorization has been issued or conduct a clinical trial in respect of such a drug unless the drug has a label that sets out the following information:

• (a) a statement indicating that the drug is an investigational drug to be used only by a qualified investigator;
• (b) the name, number or identifying mark of the drug;
• (c) the expiration date of the drug;
• (d) the recommended storage conditions for the drug;
• (e) the lot number of the drug;
• (f) the name and contact information of the holder of the authorization; and
• (g) the protocol code or identification.

Presentation of information

(2) The information required by subsection (1) to be set out on the label must be in English and in French.

Serious unexpected adverse drug reaction

34 A holder of a COVID-19 drug authorization must inform the Minister of any serious unexpected adverse drug reaction that has occurred inside or outside Canada, in respect of the COVID-19 drug that is tested in the clinical trial, as follows:

• (a) within 15 days after becoming aware of the reaction, if it is neither fatal nor life-threatening; and
• (b) within seven days after becoming aware of the reaction, if it is fatal or life-threatening.

Records

35 (1) A holder of a COVID-19 drug authorization must record, handle and store all information in respect of the clinical trial for which the authorization has been issued in a manner that allows for the complete and accurate reporting as well as the interpretation and verification of the information.

Content

(2) The holder of the authorization must maintain complete and accurate records, which include the following, in respect of a COVID-19 drug for which the authorization has been issued in order to establish that the clinical trial is conducted in accordance with good clinical practices and these Regulations:

• (a) the information and material referred to in paragraphs 20(2)(e) to (k);
• (b) records respecting each change made to the information and material referred to in paragraph (a), the rationale for each change and documentation that supports each change;
• (c) records respecting all adverse events in respect of the drug that have occurred inside or outside Canada, including the indication for use and the dosage form of the drug at the time of the adverse event;
• (d) in respect of a drug that meets the requirements of paragraphs 27(a) to (c), records respecting any serious unexpected adverse drug reaction that has occurred inside or outside Canada;
• (e) records respecting the enrolment of clinical trial subjects, including information that allows all subjects to be identified and contacted in the event that the sale of the drug may endanger the health of the subjects or other persons;
• (f) records respecting the shipment, receipt, disposition, return and destruction of the drug;
• (g) for each clinical trial site, an undertaking, signed and dated by the qualified investigator prior to the commencement of their responsibilities in respect of the clinical trial stating that
  • (i) the qualified investigator will conduct the clinical trial in accordance with good clinical practices, and
  • (ii) the qualified investigator will immediately, on discontinuance of the clinical trial, in whole or in part, by the holder, inform 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 subjects or other persons;
• (h) 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 a research ethics board for that site; and
• (i) for each clinical trial site, an attestation, signed and dated by a research ethics board, 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.

Retention period

(3) The holder — or former holder, in the case of an authorization that has been revoked in whole — of the authorization must retain all records referred to in subsection (2) for a period of 15 years.

PART 3 General

Remote written informed consent

36 (1) If a qualified investigator is not able to obtain, in person, the written informed consent of a person to participate in a clinical trial in respect of a COVID-19 medical device for which a COVID-19 medical device authorization has been issued or a COVID-19 drug for which a COVID-19 drug authorization has been issued, the qualified investigator may obtain the written informed consent remotely.

Non-written informed consent

(2) In the case where the person is not able to provide their written informed consent, the qualified investigator may obtain their non-written informed consent if the following conditions are met:

• (a) the qualified investigator reads the contents of the informed consent form to the person;
• (b) the person provides their informed consent before a witness; and
• (c) an attestation by the witness that the person has provided their informed consent is provided to the qualified investigator as soon as feasible.

PART 4 Other Clinical Trials

Exemption — certain drugs

37 (1) A person that is authorized under Division 5 of Part C of the Food and Drug Regulations to sell or import a drug for the purposes of a clinical trial — and any other person that conducts the clinical trial — is, in respect of the clinical trial, exempt from section 3.1 of the Act.

Clarification — suspension and cancellation

(2) For greater certainty, the exemption does not apply

• (a) if the authorization to sell or import the drug is suspended in its entirety; or
• (b) in respect of the conduct of the clinical trial at a clinical trial site, if the authorization to sell or import the drug is suspended or cancelled in respect of that site.

Definition of clinical trial

(3) In this section, clinical trial has the same meaning as in section C.05.001 of the Food and Drug Regulations.

Exemption — positron-emitting radiopharmaceuticals

38 (1) A person that is authorized under Division 3 of Part C of the Food and Drug Regulations to sell or import a positron-emitting radiopharmaceutical for the purposes of a study — and any other person that conducts the study — is, in respect of the study, exempt from section 3.1 of the Act.

Clarification — suspension and cancellation

(2) For greater certainty, the exemption does not apply

• (a) if the authorization to sell or import the radiopharmaceutical is suspended in its entirety; or
• (b) in respect of the conduct of the study at a study site, if the authorization to sell or import the radiopharmaceutical is suspended or cancelled in respect of that site.

Exemption — natural health products

39 (1) A person that is authorized under Part 4 of the Natural Health Products Regulations to sell or import a natural health product for the purposes of a clinical trial — and any other person that conducts the clinical trial — is, in respect of the clinical trial, exempt from section 3.1 of the Act.

Clarification — suspension and cancellation

(2) For greater certainty, the exemption does not apply

• (a) if the authorization to sell or import the natural health product is suspended in its entirety; or
• (b) in respect of the conduct of the clinical trial at a clinical trial site, if the authorization to sell or import the natural health product is suspended or cancelled in respect of that site.

Definitions

(3) The following definitions apply in this section.

clinical trial has the same meaning as in section 63 of the Natural Health Products Regulations. (essai clinique) natural health product has the same meaning as in subsection 1(1) of the Natural Health Products Regulations. (produit de santé naturel)

Exemption — medical devices

40 (1) A person that is authorized under Part 3 of the Medical Devices Regulations to sell a medical device for investigational testing — and any person that conducts the testing of the device — is, in respect of the testing, exempt from section 3.1 of the Act.

Exception

(2) The exemption does not apply in respect of any person to whom the medical device can no longer be sold as a result of a measure taken by the Minister under subsection 85(2) of the Medical Devices Regulations.

Suspension — deemed holder

41 (1) An authorization to conduct a clinical trial in respect of a drug is suspended if

• (a) the holder is deemed to hold the authorization under any of sections 180 to 182 of the Budget Implementation Act, 2019, No. 1; and
• (b) the holder’s authorization to sell or import the drug for the purposes of the clinical trial is suspended under
  • (i) section C.03.317, C.05.016 or C.05.017 of the Food and Drug Regulations, or
  • (ii) section 80 or 81 of the Natural Health Products Regulations.

Reinstatement

(2) An authorization that is suspended under subsection (1) is reinstated if the authorization referred to in paragraph (1)(b) is reinstated.

Revocation — deemed holder

(3) An authorization to conduct a clinical trial in respect of a drug or medical device is revoked if

• (a) the holder is deemed to hold the authorization under any of sections 180 to 183 of the Budget Implementation Act, 2019, No. 1; and
• (b) the holder’s authorization to sell or import the drug or device for the purposes of the clinical trial is cancelled
  • (i) in the case of a drug, under
  • (A) section C.03.319 or paragraph C.05.016(4)(b) or C.05.017(3)(b) of the Food and Drug Regulations, or
  • (B) paragraph 82(b) of the Natural Health Products Regulations, and
  • (ii) in the case of a device, under paragraph 85(2)(b) of the Medical Devices Regulations.

Partial suspensions or revocations

(4) If the authorization referred to in paragraph (1)(b) or (3)(b) is only partially suspended or cancelled, the authorization to conduct the clinical trial is suspended or revoked to the same extent.

PART 5 Transitional Provisions

Definition of Interim Order No. 2

42 In sections 43 to 52, Interim Order No. 2 means the Interim Order No. 2 Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19, made by the Minister on May 3, 2021, and published in Part I of the Canada Gazette on May 22, 2021.

Applications

43 An application for a COVID-19 medical device authorization or a COVID-19 drug authorization that was submitted to the Minister under Interim Order No. 2 before the day on which this section comes into force and in respect of which no decision has been made before that day is deemed to be an application for a COVID-19 medical device authorization or a COVID-19 drug authorization submitted under these Regulations.

Authorizations

44 A COVID-19 medical device authorization or a COVID-19 drug authorization that was issued or reinstated by the Minister under Interim Order No. 2 before the day on which this section comes into force and that has not been revoked in whole before that day is deemed to be a COVID-19 medical device authorization or a COVID-19 drug authorization issued or reinstated under these Regulations.

Approval — research ethics board

45 Any approval of a research ethics board that was obtained by a holder of a COVID-19 medical device authorization or a holder of a COVID-19 drug authorization under Interim Order No. 2 before the day on which this section comes into force is deemed to be an approval of the research ethics board obtained by the holder of a COVID-19 medical device authorization or the holder of a COVID-19 drug authorization under these Regulations.

Terms and conditions

46 Any terms and conditions that were imposed on a COVID-19 medical device authorization or a COVID-19 drug authorization by the Minister under Interim Order No. 2 before the day on which this section comes into force are deemed to be terms and conditions imposed on the COVID-19 medical device authorization or the COVID-19 drug authorization under these Regulations.

Amendment applications

47 An application to amend a COVID-19 medical device authorization or a COVID-19 drug authorization that was submitted to the Minister under Interim Order No. 2 before the day on which this section comes into force and in respect of which no decision has been made before that day is deemed to be an application to amend a COVID-19 medical device authorization or a COVID-19 drug authorization submitted under these Regulations.

Amended authorization

48 A COVID-19 medical device authorization or a COVID-19 drug authorization that was amended by the Minister under Interim Order No. 2 before the day on which this section comes into force and that has not been revoked in whole before that day is deemed to be a COVID-19 medical device authorization or a COVID-19 drug authorization amended to the same extent under these Regulations.

Suspension

49 A COVID-19 medical device authorization or a COVID-19 drug authorization that was suspended in whole or in part by the Minister under Interim Order No. 2 before the day on which this section comes into force and that has not been revoked in whole before that day is deemed to be a COVID-19 medical device authorization or a COVID-19 drug authorization suspended in whole or in part to the same extent under these Regulations.

Request — additional information and material

50 A request for additional information or material, including samples, that was made by the Minister under Interim Order No. 2 before the day on which this section comes into force is deemed to be a request for additional information or material under these Regulations.

Discontinuance

51 A notice of discontinuance provided to the Minister, or information in respect of discontinuance provided in writing to a qualified investigator, by the holder of a COVID-19 medical device authorization or a COVID-19 drug authorization under Interim Order No. 2 before the day on which this section comes into force is deemed to be a notice of discontinuance or information provided under these Regulations.

Revocation in part

52 A COVID-19 medical device authorization or a COVID-19 drug authorization that was revoked in part by the Minister under Interim Order No. 2 before the day on which this section comes into force and that has not been revoked in whole before that day is deemed to be a COVID-19 medical device authorization or a COVID-19 drug authorization revoked in part to the same extent under these Regulations.

PART 6 Consequential Amendments, Related Amendments and Coming into Force

Consequential Amendments

Certificate of Supplementary Protection Regulations

53 Subsection 1(2) of the Certificate of Supplementary Protection Regulationsfootnote 1 is replaced by the following:

Definition of authorization for sale

(2) In these Regulations and for the purposes of section 104 of the Act, authorization for sale means an authorization under the Food and Drugs Act, or any predecessor enactment relating to the same subject-matter, that permits the sale of a drug in Canada, but does not include an interim order permitting the sale of a drug under section 30.1 of that Act, a certificate issued under section C.08.015 of the Food and Drug Regulations, an exemption permitting the sale of a drug under subsection C.10.002(1) of those Regulations, or an authorization under section C.05.006, C.05.008 or C.08.010 of those Regulations, section 67 or 71 of the Natural Health Products Regulations or section 21 or subsection 24(2) of the Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations.

Regulations Amending Certain Regulations Concerning Drugs and Medical Devices (Shortages)

54 Section 8 of the Regulations Amending Certain Regulations Concerning Drugs and Medical Devices (Shortages)footnote 2 is amended by replacing the subsection 1(2) that it enacts with the following:

Definition of authorization for sale

(2) In these Regulations and for the purposes of section 104 of the Act, authorization for sale means an authorization under the Food and Drugs Act, or any predecessor enactment relating to the same subject-matter, that permits the sale of a drug in Canada, but does not include an interim order permitting the sale of a drug under section 30.1 of that Act, a certificate issued under section C.08.015 of the Food and Drug Regulations, an exemption permitting the sale of a drug under subsection C.10.002(1) or C.10.008(1) of those Regulations, or an authorization under section C.05.006, C.05.008 or C.08.010 of those Regulations, section 67 or 71 of the Natural Health Products Regulations or section 21 or subsection 24(2) of the Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations.

Related Amendments

Food and Drug Regulations

55 Subsection C.05.012(4) of the Food and Drug Regulationsfootnote 3 is replaced by the following:

(4) The sponsor shall maintain all records referred to in this Division for a period of 15 years.

Natural Health Products Regulations

56 Subsection 76(4) of the Natural Health Products Regulationsfootnote 4 is replaced by the following:

(4) The sponsor shall maintain all records referred to in this Part for a period of 15 years.

Coming into Force

Registration

57 (1) Subject to subsection (2), these Regulations come into force on the day on which they are registered.

Cessation of effect of interim order

(2) Sections 1 to 53 come into force on the day following the day on which the Interim Order No. 2 Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19, made by the Minister on May 3, 2021, and published in the Part I of the Canada Gazette on May 22, 2021, ceases to have effect.

REGULATORY IMPACT ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Issues

Clinical trials authorization pathway

The Interim Order Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19 and the Interim Order No. 2 Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19 (the Interim Orders) put in place a more flexible clinical trials pathway for COVID-19 drugs and medical devices. Interim Order No. 2 (IO No. 2) came into force on May 3, 2021, and replaced Interim Order No. 1 ([ARCHIVED] IO No. 1), which came into force on May 23, 2020. Transitional provisions carried clinical trials authorized under IO No. 1 into IO No. 2. As interim orders are temporary, action was needed to ensure that the Interim Orders’ authorizations, obligations, and oversight continue uninterrupted for trials already authorized. It was also important for the pathway to remain available for new clinical trials for drugs and medical devices related to the diagnosis, treatment, mitigation, or prevention of COVID-19 given the unpredictable evolution of the COVID-19 pandemic.

The Interim Orders also included an exemption from section 3.1 of the Food and Drugs Act (FDA) for clinical trials authorized under the existing pathways in the Food and Drug Regulations (FDR), Medical Devices Regulations (MDR) and Natural Health Products Regulations (NHPR). This new section of the FDA was brought into force concurrently with IO No. 1 and prohibits the conduct of a clinical trial without authorization. This exemption from the application of the prohibition in section 3.1 was a technical measure to maintain the status quo for these trials. Continuing this exemption in regulation was necessary to enable clinical trials authorized under these existing regulatory pathways after May 23, 2020, to continue without contravening section 3.1.

If IO No. 2 had expired without replacement, clinical trials authorized under it would have become unauthorized, and the requirements placed on authorization holders would have ceased to exist. In addition, any conduct undertaken on clinical trials under the FDR, MDR, and NHPR pathways after IO No. 2 expired would have contravened section 3.1 of the FDA.

Records retention

The Interim Orders were only able to impose an obligation to retain records for the period during which the Interim Orders were in effect (i.e. up to a maximum of one year for each Interim Order) despite the much longer retention periods under the FDR and NHPR pathways. Action was required to establish longer-term records retention periods for clinical trials authorized under the Interim Orders. The expiration of IO No. 2 without an appropriate transition could have resulted in records retention requirements for medical device or drug clinical trials authorized under the Interim Orders lapsing well before generally accepted retention periods.

The previous records retention period of 25 years for clinical trials of drugs and natural health products prescribed by the FDR and NHPR created undue regulatory burden on sponsors conducting clinical trials in Canada. Stakeholders had expressed that this requirement was overly burdensome at an administrative and financial level, and was misaligned with some jurisdictions.

Background

Clinical trials authorization pathway

Health Canada authorizes the import and sale of a drug, medical device, or natural health product (according to the clinical trial regimes in the FDR, MDR, and NHPR, respectively) for its use in a clinical trial if the trial is expected to meet its objectives and if the health product is determined to meet all quality and safety requirements. Among other requirements, Health Canada assesses available information about the drug or medical device and requires that a research ethics board review and approve the trial before it is initiated at each site. While trials are ongoing, Health Canada monitors and assesses the emerging safety data, medical device incidents, and other information. To verify that clinical trials are taking place in accordance with the Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations (the Regulations), Health Canada may also carry out routine inspections or for-cause inspections (e.g. in response to suspected non-compliance with the Regulations).

Active research and development is underway around the world to develop vaccines, diagnostics and therapies for COVID-19, the disease caused by the coronavirus SARS-CoV-2. The last stage of research and development is human clinical trials, which assess a product’s safety and efficacy. The evidence collected through trials is crucial for demonstrating that a product is effective in diagnosing, treating, mitigating, or preventing the condition, and that its benefits exceed its risks.

The Interim Orders provided an optional authorization and implementation pathway for clinical trials for drugs (pharmaceuticals and biologics, including vaccines) and medical devices (class II, III and IV) used in the diagnosis, treatment, mitigation, or prevention of COVID-19 or COVID-19 complications. The new pathway introduced efficiencies in the conduct of and access to these clinical trials.

The Interim Orders provided the Minister of Health (the Minister) with the ability to regulate the conduct of clinical trials via new authorities in the FDA that were enacted under the Budget Implementation Act, 2019, No. 1 (BIA 2019), and brought into force by Order in Council concurrently with IO No. 1. These authorities authorize the conduct of a clinical trial and allow the Minister to oversee and intervene in a clinical trial through imposing terms and conditions, requesting additional information, or suspending or revoking an authorization in whole or in part. These authorities facilitate a broader range of trials that may not otherwise have been authorized and allow the ability to further address uncertainties or mitigate risks. Other flexibilities in the Interim Orders included the following:

• Reduced administrative requirements for investigating the use of existing marketed drugs as possible COVID-19-related therapies;
• Alternate means of obtaining a patient’s informed consent;
• Broadened criteria of qualified health professionals who can carry out qualified investigator duties for drug trials, including at remote sites; and
• An expanded range of applicants who are able to apply for a COVID-19 medical device clinical trial authorization.

The Interim Orders also exempted clinical trials authorized under the existing regulatory frameworks in the MDR, FDR, and NHPR from the new FDA provision (section 3.1) prohibiting the conduct of a clinical trial without authorization. This exemption was a technical measure that enabled clinical trials authorized under these existing regulatory pathways after May 23, 2020, to continue without contravening this new conduct prohibition. Persons who held clinical trial authorizations under the FDR, MDR, and NHPR prior to May 23, 2020, have been deemed to be holders of section 3.1 authorizations under transitional provisions in BIA 2019.

As the framework in the Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations (the Regulations) covers both drugs and medical devices, the Regulations use the common term “clinical trials,” rather than the MDR’s term “investigational testing.”

Records retention

Under Part C, Division 5 of the FDR and Part 4 of the NHPR, sponsors of clinical trials were required to maintain all records referred to in these respective regulations for 25 years. This timeframe was introduced in 2001 into the FDR when the current clinical trial framework for drugs involving human subjects was introduced in Part C, Division 5. The retention period aligned with industry standards of that time, and was established to protect trial participants from undue risk. These same requirements were included in the NHPR when they were made in 2004. However, feedback received from consultations in 2017–2018 and the evolution of good clinical practices has led Health Canada (the Department) to determine that a lower records retention period for sponsors is more appropriate.

In the (ARCHIVED) Fall Economic Statement 2018, the Government of Canada publicly committed to creating business efficiencies by reducing regulatory burden and simplifying government regulations.footnote 5 Under this theme, and as an early deliverable, the Government proposed to reduce the duration of clinical trial records retention requirements, thereby lessening the cost burden on clinical trial sponsors and investigators. The proposal was also included as a commitment in the Health and Biosciences: Targeted Regulatory Review – Regulatory Roadmap under the Global Systems theme.

Objectives

The objectives of the Regulations are the following:

• Maintain the provisions of the Interim Orders to ensure that clinical trials for COVID-19 drugs and medical devices authorized under the Interim Orders, and clinical trials authorized under the existing frameworks in the MDR, FDR and NHPR on or after May 23, 2020, can continue without disruption; and
• Reduce the burden associated with the 25-year clinical trial records retention period for drugs and natural health products by amending the FDR and NHPR.

By continuing the framework established in the Interim Orders for all COVID-19 drug and medical device clinical trials, the Regulations

• provide continuity for clinical trials already submitted or authorized under the Interim Orders;
• carry over the authorization scheme set out in the Interim Orders allowing for new applications to be made;
• provide continuity of all flexibilities established in the Interim Orders;
• maintain and clarify requirements of authorization holders, including record-keeping requirements; and
• maintain oversight of clinical trials commenced under the Interim Orders.

By lowering the records retention period for clinical trials of drugs and natural health products from 25 to 15 years, the Regulations

• more closely align Canada’s records retention period with lower records retention periods in other jurisdictions, e.g. Australia (15 years), France (15 years) and Switzerland (10 years);
• decrease the cost and administrative burden on stakeholders conducting clinical trials in Canada; and
• contribute to making Canada a more favourable environment for conducting clinical trials.

Description

Clinical trials authorization pathway

The Regulations carry over the provisions of the Interim Orders into Governor in Council regulations, with some changes that are discussed below.

The Regulations regulate the importation and sale of drugs and devices for the purposes of clinical trials in relation to COVID-19, and the conduct of those clinical trials. The Regulations maintain the more flexible authorization and implementation pathways established in the Interim Orders for clinical trials of pharmaceutical drugs, biologic drugs (including vaccines, blood and blood components), and Class II, III and IV medical devices involving human subjects in relation to the diagnosis, treatment, mitigation, or prevention of COVID-19. The associated obligations and oversight under the Interim Orders will also continue to apply under the Regulations.

As an alternative to the requirements in the FDR and MDR, the sponsors of clinical trials for COVID-19 drugs and medical devices may opt to proceed through the pathway set out in the Regulations. The trials may assess the use of existing, marketed products in Canada as COVID-19–related therapies, or they may assess new COVID-19–related therapies currently under development. The flexible authorization pathway provided for in the Regulations will remain available for new clinical trials, with the associated obligations and oversight.

Maintaining this framework will continue to facilitate the launch of COVID-19 drug or medical device clinical trials by reducing administrative burden relating to trial-related authorizations and implementation, while still upholding the requirements necessary for the health and safety of clinical trial participants and the validity of trial data.

It is anticipated that the Regulations will remain in force until Health Canada’s proposed Modernization of the Regulation of Clinical Trials initiative is in place. The proposed modernization framework would transition all clinical trials, including those under the Regulations as well as those under the existing frameworks in the FDR, MDR and NHPR, into a modernized framework. It is anticipated that the modernized framework would include some of the flexibilities under the Regulations for a broader range of clinical trials.

Flexible pathway

The authorization pathway provided in the Interim Orders and now in the Regulations was designed to better facilitate clinical trials during the COVID-19 public health emergency by increasing efficiencies and reducing the administrative burden of certain requirements. It also makes it easier to set up and run multicentre trials.

The pathway increases flexibility by, for example, expanding the scope of the definition of “qualified investigator” for clinical trials for drugs to permit additional licensed healthcare professionals, such as nurse practitioners, to fill that role. Under the current FDR, only physicians or dentists can become qualified investigators. This flexibility will help to facilitate multicentre trials as well as trials in locations, such as remote Northern communities, where there is a scarcity of physicians available to oversee them.

At present, the MDR allows only manufacturers and importers of medical devices to apply for an investigational testing authorization. The pathway provided for in the Interim Orders and the Regulations enables an investigator, independent of the device manufacturer, to apply for a clinical trial authorization in addition to a manufacturer and importer.

The Regulations outline two alternate means of obtaining informed consent when potential drug or medical device clinical trial participants are unable to consent in person or in writing. The first permits remote, written informed consent of a potential participant when they are unable to be in the same location as the qualified investigator. The second permits non-written informed consent when a potential participant cannot provide written informed consent. These measures will continue to support multicentre trials, including those with sites in remote locations, where the qualified investigator and potential participant are in different locations and consent may be obtained, for instance, via videoconference. These measures will also continue to reduce barriers to the provision of consent given restrictions currently in place due to COVID-19; for instance, infection control practices in hospitals may prohibit people who are in isolation from accessing paper.

The pathway further reduces the burden of certain requirements involving communication with Health Canada regarding changes that occur over the course of a trial. This includes requiring amendment applications only for significant changes carrying potentially high risks. The Minister also continues to have the ability to partially suspend or revoke the authorization of a trial, which, for example, could allow the Minister to suspend one arm, or treatment group, of a randomized trial if needed, while allowing the rest of the trial to continue so that other patients can still continue to receive a promising therapy. This ability will continue to offer increased flexibility for the type of innovative trial designs being pursued for COVID-19 drugs and medical devices.

Oversight of clinical trials

As the health and safety of clinical trial participants remain as important as ever, the Regulations, like the Interim Orders, continue to provide the Minister with certain authorities to oversee and intervene in clinical trials, as needed, in the best interest of clinical trial participants. These abilities include the use of terms and conditions on clinical trial authorizations, which would be applied on a case-by-case basis to address uncertainties and mitigate risks. Terms and conditions could include requiring more frequent safety reporting; monitoring of specific populations because of potential increased risk (e.g. children); or additional information to characterize and mitigate newly identified risks. Another oversight ability permits the Minister to request additional information in relation to a clinical trial application or authorization that may be necessary to enable the Minister to determine whether to issue, amend, suspend or revoke (in whole or in part) the authorization.

Regarding other requirements for clinical trials, this pathway has several similar requirements to those in the FDR and the MDR. These include requirements for incident reporting, labelling, record keeping, and good clinical and manufacturing practices specifically for drug clinical trials. However, the pathway has reduced labelling and record-keeping requirements for marketed drugs that are already authorized in Canada for other uses and that are used in COVID-19 drug or medical device clinical trials within the standard of medical practice.

As with all clinical trials conducted in Canada, Health Canada will monitor the safety of the drugs and devices used under the Regulations and will take immediate action, including the suspension or revocation of authorizations, if required to protect the health and safety of trial participants.

Exemption from section 3.1 of the FDA

The Regulations also continue to exempt clinical trials authorized under the existing regulatory frameworks in the MDR, FDR, and NHPR from the new FDA provision prohibiting the conduct of a clinical trial without authorization. This exemption ensures that clinical trials operating under the existing regulatory frameworks can continue to do so without contravening the prohibition in section 3.1. Authorization holders will continue to hold their existing authorizations under the regulatory frameworks under which they were approved. New clinical trials may also continue to be approved under the MDR, FDR and NHPR.

Changes from Interim Order No. 2

In comparison to IO No. 2, some minor changes have been made to certain provisions to clarify the Regulations. These changes

• clarify that the classification framework for medical devices in the MDR applies to the Regulations;
• clarify the types of information or material that, if changed significantly, would require an amendment to a COVID-19 medical device authorization. This change better aligns the Regulations with the guidance for the Interim Orders, and with practice; and
• improve the wording of the provisions related to amendments to authorizations (sections 8 and 24) to align with good drafting practices and to more accurately describe the obligations of authorization holders in these situations.

Transitional provisions

Transitional provisions have been included in the Regulations to ensure that clinical trials that were authorized under the Interim Orders will be able to continue without disruption under the Regulations. For example,

• authorizations that were issued, reinstated, or amended under IO No. 2 are deemed to be authorizations issued, reinstated, or amended under the Regulations;
• applications (including new applications and applications for amendments) that were submitted under IO No. 2 and not finalized by the Minister are deemed to be applications submitted under the Regulations;
• terms and conditions imposed under IO No. 2 are deemed to be terms and conditions imposed under the Regulations; and
• suspensions and revocations made under IO No. 2 are considered to be suspensions and revocations made under the Regulations.

Note that transitional provisions in IO No. 2 carried clinical trials authorized under IO No. 1 into IO No. 2.

Consequential amendment to the Certificate of Supplementary Protection Regulations

The Regulations include a consequential amendment to the Certificate of Supplementary Protection Regulations (CSPR) to exclude authorizations under section 21 and amendments under subsection 24(2) of the Regulations from the definition of “authorization for sale” in the CSPR, just as clinical trial authorizations and amendments under sections C.05.006 and C.05.008 of the FDR and sections 67 and 71 of the NHPR are currently excluded. In addition, a minor amendment was made to ensure consistency between the English and French and to avoid repetition.

Records retention

The records retention requirements of the Regulations differ from those of the Interim Orders due to the inability to put into place records retention periods in the Interim Orders that extended beyond their life span (i.e. one year for each Interim Order). In the Regulations, holders (and former holders) of clinical trial authorizations in respect of COVID-19 drugs are required to retain records for 15 years, a reduction from the previous requirement of 25 years in the FDR. The Regulations require holders (and former holders) of clinical trial authorizations for COVID-19 medical devices to retain distribution records for the longer of the projected useful life of the device, or two years after the date on which the authorization holder took possession, care or control of the device in Canada. As the MDR does not specify a retention period for clinical trial records for medical devices, only that they must be retained as a condition to sell a medical device, the Regulations do not impose a specific, uniform period for clinical trial records retention for medical devices. The Regulations require authorization holders to retain such records for the duration of the authorization.

The longer records retention periods in the Regulations will apply to clinical trials previously authorized under IO No. 2 (which includes those authorized under IO No. 1 as per transitional provisions in IO No. 2).

In addition to prescribing a records retention period of 15 years for sponsors of COVID-19 drug clinical trials authorized through the Interim Orders, the FDR and NHPR have been amended to reduce the records retention period for clinical trials of drugs and natural health products from 25 years to 15 years. The amendments apply to all clinical trials with ongoing records retention obligations prior to these amendments coming into force. The amendments also apply to all new clinical trials authorized under the FDR and NHPR after these amendments come into force.

Regulatory development

Consultation

Clinical trials authorization pathway

Consultation prior to Interim Order No. 1

The Department held consultations in spring 2020 for IO No. 1. The Department also held targeted consultation sessions to seek input on some of the concepts underlying the Interim Orders from key stakeholders, including research ethics boards across Canada; provincial governments; industry associations in the drug, medical device and biotechnology sectors; and the Canadian Institutes of Health Research (CIHR).

Many aspects of the Interim Orders have implemented suggestions from the consultations regarding the clinical trials modernization initiative. This initiative has been discussed with stakeholders via regulatory innovation road shows, online consultation on Agile regulations for advanced therapeutic products and clinical trials, and various other consultations and outreach in 2019 and early 2020.

Consultation post-Interim Order No. 1

Since spring 2020, Health Canada has been leading engagement sessions on clinical trial oversight and implementation in Canada with participation from CIHR, the Canadian Association of Research Ethics Boards (CAREB) and research ethics boards that frequently review clinical trials in Canada. Through this initiative, policy makers, regulators, funders and oversight bodies are collaborating and sharing information on clinical trials. Further, the IO No. 1 was presented at several external stakeholder engagement sessions (e.g. National Association of Pharmacy Regulatory Authorities [NAPRA]). These additional stakeholder engagements informed the development of the Regulations. Additionally, the Interim Order pathway was in effect from May 2020 until the coming into force of the Regulations, giving stakeholders and the Department experience with the framework.

On December 14, 2020, Health Canada hosted two virtual consultation webinars, in both official languages, to discuss the proposal to transition IO No. 1 into regulations and reduce records retention requirements for drugs and natural health products. A total of 98 external participants attended with an approximately even mix of industry and non-industry stakeholders (academics, health professionals, provincial and territorial stakeholders). Written comments on the proposal were also invited. Stakeholders were generally supportive of the proposal.

Records retention

During consultations conducted in 2017–2018 to inform the FDR guidance on clinical trials, stakeholders in the clinical trial sector (including national non-profit research networks, a major clinical trial service provider and a prominent multinational pharmaceutical company) raised concerns over the 25-year records retention requirement for clinical trials of drugs involving human participants. Industry expressed that this requirement was overly burdensome at an administrative and financial level, and misaligned with other jurisdictions. Similar concerns were raised again by stakeholders during consultations conducted through the targeted sectoral regulatory review of the health and biosciences sector.

The reduction of the records retention period was discussed at the technical consultation on December 14, 2020. A Notice of Intent on records retention was published in the Canada Gazette on December 12, 2020, and consultations concluded on January 25, 2021. Sixteen stakeholder responses were received. Four respondents were in favour of maintaining the 25-year retention period due to concerns regarding patient safety associated with specific types of clinical trials (e.g. oncology and pediatrics), and reducing the ability for clinical researchers to use data for reanalysis. Two academic stakeholders were in favour of retention periods longer than the current 25 years, citing concerns over the loss of data with the decrease in clinical trials records retention.

Additional targeted consultations took place during the week of March 8, 2021. Health Canada held four consultations with stakeholders from patient safety organizations, academic researchers, medical professional groups and industry. A total of 44 stakeholders participated in the consultations. The majority of stakeholders were generally supportive of the 15-year retention period and expressed that this change will reduce the administrative burden of keeping paper records at investigator sites. Industry sponsors may choose to retain records for longer periods for corporate memory or in multijurisdictional trials with the European Union (EU) where the suggested standard is 25 years. Despite this, sponsors expressed there remains sufficient benefit and cost savings for this proposal, particularly for clinical trial sites and qualified investigators in Canada. Stakeholders further expressed that including exceptions that would maintain a longer retention period for certain types of clinical trials would add administrative complexity and burden, as they would need to manage different requirements based on the type of trial or participant. Additionally, maintaining exceptions to the 15-year requirement would be misaligned with other jurisdictions that do not have different retention periods for different types of clinical trials. Academic stakeholders maintained their support for the existing 25-year retention period.

Exemption from prepublication

An exemption from prepublication of the Regulations in the Canada Gazette, Part I, was sought for the following reasons:

• The Regulations do not deviate significantly from the Interim Orders. A few changes were required due to the limitations associated with the Interim Orders (i.e. record keeping and distribution record requirements that were only applicable during the life of the Interim Orders were adjusted to align more closely with requirements for clinical trials under the FDR and MDR). Some amendments were also made for clarity and transition purposes.
• The Regulations are intended as a temporary measure to maintain the framework and exemptions set out in the Interim Orders. The intention is for the Regulations to remain in force until the proposed Modernization of the Regulation of Clinical Trials initiative is in place. The Regulations may be repealed when the proposed modern framework is introduced. The Modernization of the Regulation of Clinical Trials initiative is a commitment under the Health and Biosciences Sector Regulatory Review Roadmap and is listed under Health Canada’s Forward Regulatory Plan.
• It is anticipated that manufacturers and other stakeholders will be minimally affected by the Regulations, as the pathway in the Interim Orders and the Regulations is optional. Stakeholders were briefed on IO No. 1 via information sessions after it came into force, and were also consulted on the plan to transition the Interim Orders into regulations.
• The overall cost implications for stakeholders are anticipated to be low, with anticipated cost savings for industry resulting from the reduced records retention requirement in the FDR and the NHPR.
• The reduction in the records retention period is expected to deliver benefits and not introduce more burden to stakeholders, while still offering an appropriate level of patient safety oversight for Canadians. Furthermore, Health Canada has engaged in previous stakeholder consultations for this amendment in 2017–2018 and two rounds of consultations in 2020–2021 to validate previous feedback that this amendment is expected to deliver benefits as initially scoped under the Health and Biosciences Sector Regulatory Review Roadmap. Stakeholders would not have to do anything differently to comply with the requirement; the period of time that compliance is required would simply be shorter.

Modern treaty obligations and Indigenous engagement and consultation

The Regulations do not impact Government of Canada’s obligations in relation to rights protected by section 35 of the Constitution Act, 1982, or modern treaties.

Instrument choice

Health Canada considered the following options.

1. No action

If no action was taken, upon the expiry of IO No. 2,

• clinical trials authorized under the Interim Orders would become unauthorized;
• clinical trials authorized under the existing frameworks in the MDR, FDR and NHPR on or after May 23, 2020, would no longer be exempt from the prohibition against conducting clinical trials in section 3.1 of the FDA;
• the obligations imposed by the Interim Orders would no longer apply to clinical trials authorized under those orders, and the Minister would lose many oversight authorities for these trials;
• new clinical trials would be unable to proceed under the more flexible pathway; and
• records retention requirements for medical devices and drugs in clinical trials authorized under the Interim Orders would lapse well before generally accepted retention periods.

The only means by which to maintain the optional authorization pathway and allow clinical trials authorized under the regular pathway in the FDR, MDR, and NHPR to continue without disruption is either through transitioning the Interim Orders to Governor in Council regulations, or continuing to issue Interim Orders.

2. Creation of further interim orders

While the FDA leaves the possibility open for an interim order to be remade, the threshold for making an interim order — the Minister must believe immediate action is required to deal with a significant risk, direct or indirect, to health — must persist at the time that it is made. Interim orders, when approved by the Governor in Council, are only valid for one year, which does not provide stability or predictability to sponsors of clinical trials.

3. Creation of regulations

The Regulations maintain the provisions of the Interim Orders in a manner that provides predictability and stability to sponsors of clinical trials. The Regulations also codify the exemption from section 3.1 of the FDA, ensuring clinical trials authorized under the regular pathway in the FDR, MDR, and NHPR can continue. The Regulations allow for longer-term records retention periods to be set for clinical trials authorized under the Interim Orders and future clinical trials authorized under the Regulations. While time-limited regulations were an option, the permanent status of the Regulations provides stability for clinical trials conducted in Canada and avoids the risks associated with the Regulations expiring before a new framework is in place.

Regulatory analysis

Benefits and costs

The Regulations transition the provisions of IO No. 2 to maintain, without disruption, the framework and exemptions set out in IO No. 2 until the proposed Modernization of the Regulation of Clinical Trials framework is in place. The baseline for this analysis is the existing FDR or MDR framework as the standard authorization pathway for drugs and medical devices; therefore, any flexibilities and incremental changes provided in the Interim Order authorization pathway and brought forward into the Regulations are measured against the FDR or MDR pathway.

Health Canada sent a costing survey to stakeholders on December 14, 2020. Six responses were received, with three indicating their intent to file for COVID-19 clinical trials. It is estimated there could be four COVID-19 clinical trials filed under the Regulations. Respondents did not indicate the timeline to submit these trials. To be conservative in our cost approach, it is assumed that these clinical trials will be filed in the first year.

Benefits and costs of the Regulations

As of August 18, 2021, there were over 5 566 clinical trials testing drugs and vaccines for the coronavirus disease worldwide. Of these, 666 are already in phase IV.footnote 6 As of August 18, 2021, Canada has approved 138 COVID-19 clinical trials, of which 51 were authorized under the Interim Orders.

COVID-19 has placed a significant burden on the healthcare system, both in terms of human resources and sufficient access to drugs and devices. The Regulations continue to support the development of safe and effective therapies to mitigate the impact of COVID-19 and its variants on the healthcare system.

Expanding the scope of qualified investigators for drug clinical trials and who can apply for medical device clinical trial authorizations

The Regulations maintain the flexibilities, which allow COVID-19 drug or medical device clinical trials to be as efficient as possible, so that safe and effective therapies can be brought to market and made available to Canadians as quickly as possible. By expanding the scope of practitioners that could qualify as qualified investigators for drug clinical trials (already realized for medical device clinical trials), the Regulations allow for the continuation of trials in rural communities where physician availability is limited.

As stated by a stakeholder, broadening the criteria of qualified investigator allows the sponsor of clinical trials to quickly identify healthcare partners in the community. For example, in conducting clinical trials with children with COVID-19 symptoms, facilitating partnerships with a variety of healthcare professionals to conduct this research is critical in obtaining a sufficient number of participants in the sample.

Furthermore, the flexibility of this measure could potentially reduce the costs for sponsors associated with having to hire a physician to oversee the trial as well as the cost savings from a shorter recruitment period.

The Interim Orders also expanded the scope of who could apply for a medical device clinical trial authorization, which could attract more medical device trials in a hospital setting.

Alternate means of informed consent

The flexibility of this provision allows for a faster recruitment and higher number of participants to participate in clinical trials in response to COVID-19. This is important for critical research especially where the trials are conducted remotely or in the presence of strict infection control measures in hospitals. With this provision, the sponsors benefit from reducing the burden on their patients, increasing patient safety during the pandemic by limiting hospital visits and leveraging digital technologies to document informed consent. However, there are potential costs required to set up the systems, for example, to provide guidance and training employees to enable this method of consent. Nonetheless, as indicated by a stakeholder, the benefits would likely outweigh the costs.

Reducing the burden of certain requirements in communicating with Health Canada regarding changes that occur over the course of a trial

There are overall cost savings for industry as a result of reducing the burden of certain requirements in communicating with Health Canada; however, the cost savings may vary among the sponsors. Stakeholders indicated the cost savings could range from minimal (e.g. internal documentations are to be maintained regardless) to significant (e.g. filing administrative notifications that are non-safety related could take up about a quarter of the administrative resources).

Additionally, it is estimated that Health Canada could save at least three hours of regular review per file from this provision.

Ability to partially suspend or revoke the authorization of a clinical trial

It is difficult to estimate the cost savings from this requirement, as this flexibility was carried over from the Interim Orders and did not exist under the FDR or the MDR.footnote 7 The cost savings for the industry from this flexibility is expected to be broad depending on the complexity of the trial and which part of the trial is subjected to the suspension or revocation. There is a general recognition from stakeholders that the savings could be significant due to the potential of not having to close the entire trial.

Furthermore, the provisions would allow for the trials on potentially life-saving treatments to continue while other parts of the trial are suspended. This could provide life-saving treatment, especially for trials to combat COVID-19 and its variants.

From Health Canada’s perspective, the ability to suspend or revoke the authorization of a clinical trial in whole or in part does not lead to cost savings. The Department anticipates there may be an increase in the workload due to regulatory consideration and additional review. The process to decide whether an arm of a trial or the entire trial is to be suspended or revoked requires the same degree of review time (60–70 hours or $4,800–$5,600) depending on the complexity of the trial. As of August 18, 2021, 51 clinical trials have been authorized under the Interim Orders and none has been subjected to this partial suspension or revocation. It is uncertain how many may benefit from this provision if only four COVID-19 trials are expected to be filed under the Regulations.

Terms and conditions

BIA 2019 enacted new authorities under the FDA which granted the Minister authority to impose and amend terms and conditions on clinical trial authorizations. Out of the 51 clinical trials authorized under the Interim Orders, one trial has been authorized with terms and conditions. Those terms and conditions set out the following requirements:

• Providing compatibility results;
• Providing preliminary and final results of trial phases; and
• Providing Data and Safety Monitoring Board (DSMB) recommendations.

Given that four COVID-19 drug or device clinical trials are expected to apply under the Regulations, conservatively, it’s estimated that one trial may be subjected to terms and conditions. Based on the above requirements, it’s expected that there will be about five reports to be submitted to Health Canada. Assuming that industry already has the requested information and that it costs $100 for the sponsor to produce a report, i.e. to assemble, format and email the information, it is estimated that the cost of terms and conditions to industry would be the following: cost = $100 × 5 = $500.

In addition, Health Canada is required to review these reports at an incremental cost of approximately $23,000 per term and condition issued. It is recognized that the incremental costs to both the industry and Health Canada could be higher if the pandemic continues, or the need to conduct more clinical trials for drugs and medical devices to combat COVID-19 increases.

In the event of an incident related to a COVID-19 medical device, information must be submitted to Health Canada as described in the Interim Orders

This requirement contributes to ensuring the health and safety of Canadians. It requires that a holder of a COVID-19 medical device clinical trial authorization report the incident to the Minister within 10 days after becoming aware of an incident inside or outside Canada involving a COVID-19 medical device for which the authorization has been issued. There are potential costs to the industry to report and to Health Canada to review and assess the report; however, to date, the Department has not received any incident reports related to a COVID-19 medical device clinical trial.

Reducing records retention for all drugs and natural health products clinical trials

The amendment to reduce the records retention period from 25 years to 15 years for clinical trials of drugs and natural health products is not expected to create any additional administrative and financial burden on industry. There is already a requirement to retain records, and organizations will already have incurred the same start-up costs for retaining records, whether it is for 15 or 25 years. A reduction in the records retention period is expected to result in benefits for organizations conducting clinical trials through a decrease in administrative and financial burden (i.e. salary, storage costs, etc.). The reduction in the records retention period is a commitment from the 2018 Fall Economic Statement.

In December 2020, Health Canada conducted a costing survey with industry on the impacts of this proposal. Based on this survey, and despite a low number of respondents, Health Canada’s analysis estimated an annual cost of retaining records per clinical trial to be $2,900. A cost savings of approximately $7,400 per clinical trial was found, which represents the net present value cost of retaining records over 25 years minus the net present value cost over 15 years, discounted at 7%.

A supplementary survey was sent to stakeholders in March 2021. The response rate to this survey was slightly better than the December 2020 survey. The same methodology as that for the previous survey was used, and the annual cost of retaining records was found to be $1,400 per clinical trial. A cost savings of approximately $3,500 per clinical trial was found, which represents the net present value cost of retaining records over 25 years minus the net present value cost over 15 years, discounted at 7%.

Health Canada authorizes approximately 1 200 clinical trials per year on average, based on data provided by the Biologic and Radiopharmaceutical Drugs Directorate (PDF) and Therapeutic Products Directorate (PDF). Using the two cost savings estimates of $7,400 and $3,500 per clinical trial respectively results in a cost-saving range estimate at between $8,880,000 and $4,240,000 per year. Due to the low sample size and high variation in estimates provided by stakeholders, a precise cost saving is not possible at this time, but it is assumed to fall within this range.

The yearly cost savings presented above represent ongoing savings since it is based on clinical trials starting when the Regulations come into force. In addition, the Regulations also impact clinical trials that are underway (i.e. authorized up to 24 years ago). Each year in the past has a different savings total because each year has a shorter period of discount rates applied and may also have less than 10 years left in the previous 25-year retention requirement. Summing these yearly estimates results in a cumulative cost savings estimate of between $372 million and $177 million for all clinical trials commencing in the past 24 years.

Other costs to the Government

Assuming that there will be four COVID-19 clinical trials filed under the Regulations, the estimated cost to the Department is about $116,000, which includes regulatory review, authorization, review of application amendments and site inspections. It is also recognized that additional resources may be required due to accelerated review time for COVID-19 drug or medical device clinical trials (14 days) while maintaining current review time (30 days) for all clinical trials authorized under the FDR and MDR pathways. Health Canada will manage resources, if required, internally.

Total quantifiable benefits and costs

With the assumption that four COVID-19 clinical trials for drugs and medical devices will be filed under the Regulations in the first year, the total quantifiable cost is estimated to be about $139,500. The actual incremental costs could vary considerably depending on how many applications for COVID-19 drug or medical device clinical trials will be filed beyond the first year of the transition period. However, as this is an optional pathway, sponsors still have the standard authorization pathway through the FDR and MDR frameworks.

The total quantifiable benefits from the reduction in the records retention period consist of two cost savings; ongoing and retrospective. The ongoing cost savings are estimated to be in the range of $8,880,000 and $4,240,000 per year or $62 million and $30 million total present value over 10 years based on the average of 1 200 clinical trials per year. Retrospective cost savings for trials up to 24 years ago are estimated to be between $372 million and $177 million based on the assumption that the average of 1 200 clinical trials per year is representative over the analysis period (past, present, and future). The combined savings over the first 10 years is between $434 million ($372 million + $62 million) and $207 million ($177 million + $30 million).

Small business lens

It is expected that small businesses will benefit from the Regulations, as they expand the scope of the definition of qualified investigators for drug clinical trials and who can apply for medical device clinical trial authorizations.

Furthermore, the authorization and implementation pathway provided by the Regulations is optional. It offers flexibilities for sponsors of clinical trials for COVID-19 drugs and medical devices that are not available under the existing FDR (Part C, Division 5) or the MDR (Part 3) frameworks. While this flexibility is not unique to small businesses, it will still allow them to use the regulatory framework that is best suited to their needs and situation.

One-for-one rule

Health Canada is seeking an exemption from the one-for-one rule, as the Regulations address a pandemic that threatens human health. They thus meet the criteria for an exemption from the Red Tape Reduction Act for regulations in an emergency or exceptional circumstance, as provided for in the Red Tape Reduction Regulations.

It is anticipated that the stand-alone Regulations would remain in force until the proposed Modernization of the Regulation of Clinical Trials initiative is implemented. This initiative could transition all clinical trials, including those under the Regulations as well as those under the existing frameworks in the FDR, MDR and NHPR, into a modernized framework under the new FDA authorities that came into force concurrently with IO No. 1.

Terms and conditions that have been imposed on one clinical trial authorized under the Interim Orders include reporting requirements that would be considered an administrative burden. The terms and conditions require the sponsor to forward information, data, results and Data and Safety Monitoring Board (DSMB) recommendation to Health Canada. At $100 per report, with an estimated total of five reports to be submitted for one trial, the estimated total cost is $500 (2021 dollars). For the purpose of the one-for-one rule, the administrative burden cost is assumed to be incurred for only one year and real values in 2012 price levels are used representing $89 (2012 dollars) per report. The annualized administrative cost is estimated at $34 (2012 dollars) calculated in the manner required by the Red Tape Reduction Regulations. If the pandemic were to last longer and more COVID-19 drug and medical device clinical trials were authorized under the Regulations, the administrative burden cost would be higher.

Table 1: One-for-one rule

Values to report in the Regulatory Impact Analysis Statement
Annualized administrative costs	$34
Annualized administrative costs per business	$34

Regulatory cooperation and alignment

There is no one standard for clinical trial regulations across international jurisdictions. Differences exist among them due to the unique regulatory landscape of each jurisdiction. That said, the Regulations are aligned with some best practices in other jurisdictions described below.

The flexibilities included in the Regulations are already in place in other jurisdictions for general clinical trials (e.g. reduced administrative requirements for already marketed drug products is a risk-based approach recommended by the Organization for Economic Cooperation and Development [OECD]). These flexibilities are key to facilitating COVID-19 drug and medical device trials, and align with the EU clinical trial regulations and the OECD-recommended model for adopting risk-based approaches. In addition, terms and conditions are common authorities; for example, they are used in the Medicines and Healthcare Products Regulatory Agency (United Kingdom), the European Union, and SwissMedic clinical trial regulations.

The Regulations align COVID-19 drug and medical device clinical trial regulations with some international partners. For example, amending applications for significant changes only is similar to the U.S. Food and Drug Administration requirements. In addition, many international regulators also have expedited review of COVID-19 drug trials and offer alternative methods of obtaining informed consent.

Records retention

Canada’s previous 25-year records retention period for clinical trials of drugs and natural health products was significantly higher than similar requirements from a number of Canada’s international regulatory partners. Australia, France, the United Kingdom, and the United States maintain records retention periods of 15 years or less following completion or discontinuation of the trial. Australia and France require a 15-year minimum time period and Switzerland requires a 10-year time period. The United Kingdom requires a time period of 5 years and the United States requires 2 years. The United States and the United Kingdom’s requirements, however, begin following marketing authorization and not the completion or discontinuation of a trial. The total retention period in these countries generally aligns with Health Canada’s 15-year period. General timelines for drug development in the United States and the United Kingdom are between 10–15 years prior to market authorization, plus an additional retention period of 2 and 5 years respectively following market authorization. The European Commission maintains a retention period of 25 years following completion of a clinical trial. However, this standard remains voluntary and is subject to member states’ own record-keeping policies.

Addressing this misalignment helps improve Canada’s competitiveness internationally and could allow Canada to attract more trials and develop new innovative drugs for the Canadian market without compromising the health and safety of Canadians. The reduced records retention period more closely aligns Canadian drug clinical trial records retention requirements with those found in other jurisdictions.

Health Canada seeks to align with provincial and territorial requirements for patient medical records. The clinical trials records retention proposal will not supersede longer retention periods for patient records, which are set as part of the practice of medicine.

Strategic environmental assessment

In accordance with the Cabinet Directive on the Environmental Assessment of Policy, Plan and Program Proposals, a preliminary scan concluded that a strategic environmental assessment is not required.

Gender-based analysis plus (GBA+)

COVID-19 was found to have various direct and indirect socio-economic and health-related impacts on persons of different genders. As well, other factors affecting vulnerability to the disease include increased age, individual conditions (e.g. pre-existing medical conditions), social conditions (e.g. lower socio-economic status, residence in long-term care facilities or crowded/remote locations, homelessness, substance use disorder, race/ethnicity, immigration or refugee status), and certain occupations (e.g. healthcare workers, emergency workers, workers who have a high degree of social contact, international business travellers).footnote 8

For example, when the Government of Ontario announced a state of emergency in March 2020 that resulted in the closure of nonessential businesses, twice as many women between the ages of 25 and 54 were left unemployed as men. For those who remain employed, challenges related to childcare have been encountered. In most provinces, a limited supply of licenced childcare options has often led to one parent, normally the mother, having to abandon their employment.footnote 9

Socio-economic aspects show that people living in poverty or earning lower incomes are more impacted than those with a higher income. Some examples include homeless people forced from parks with no place to go,footnote 10 shelters deemed to be unsafe,footnote 10 less access to health care,footnote 11 unstable employment,footnote 11 and less ability to stockpile food and other cleaning supplies.footnote 11

According to an article in the Canadian Medical Association Journal, Indigenous communities may be at greater risk of developing severe symptoms and dying of COVID-19, given that a number of existing conditions in communities, such as poor access to clean water, limited health infrastructure and overcrowding, could all contribute to spreading the disease. Other socio-economic considerations are also known to affect the health of Indigenous peoples and communities.footnote 12 COVID-19 infection rates and deaths are sensitive to variables like income, employment, housing, and language, which are frequently present to varying degrees in Indigenous communities.

Based on data reported up to April 23, 2021, the largest bias for all Canadians is the impact of age and health conditions on the severity of the disease. Of all the deaths attributed to the COVID-19 virus in Canada, just under 96% occurred in individuals 60 years and over.footnote 13

There are no unintended gender-based analysis plus implications for the Regulations. The Regulations ensure that trials that benefit identified at-risk populations can continue uninterrupted when IO No. 2 expires. Flexibilities for COVID-19 drug or medical device trials may help certain sub-populations participate in studies through flexible informed consent, enabling greater decentralization of care, and reducing burden for trials studying off-label use of already marketed drugs. Health Canada’s Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Sex Differences recommends clinical trials enroll subjects representative of the population(s) expected to use the therapeutic product. As COVID-19 more seriously affects individuals who are aged, or have compromised immune systems, the Regulations are expected to assist these populations in accessing therapies related to COVID-19.

Rationale

Flexible pathway

Transitioning the provisions of IO No. 2 into the Regulations will ensure that clinical trials for COVID-19 drugs and medical devices authorized under the Interim Orders, as well as clinical trials authorized under the existing frameworks in the MDR, FDR, and NHPR as of May 23, 2020, can continue without disruption. The Regulations also ensure that the obligations of authorization holders are maintained, including by providing for longer-term records retention periods. The pathway provided for in the Interim Orders and the Regulations remains open to new clinical trials for COVID-19 drugs and medical devices to continue Canada’s response to the COVID-19 pandemic.

Records retention

Reducing the records retention period for all clinical trials of drugs and natural health products favours the competitiveness of the Canadian clinical trial industry internationally, and helps support the development and submission of new drugs in the Canadian market (i.e. increased access to novel therapies). The amendments made to the FDR and NHPR through the Regulations reflect stakeholders needs while still offering an appropriate level of patient safety oversight for Canadians.

Implementation, compliance and enforcement, and service standards

The provisions of the Regulations pertaining to the transitioning of the Interim Orders will come into force when IO No. 2 ceases to have effect. IO No. 2 will be repealed by ministerial order, which will bring these provisions into force before the default date of expiration of IO No. 2 in May 2022. The amendments to the FDR and NHPR to reduce the records retention period came into force upon registration.

As the Interim Orders have been in place since May of 2020, implementation of the Regulations will largely remain the same. Guidance on the implementation of the Interim Orders for clinical trials of COVID-19 medical devices is outlined in Health Canada’s Guidance on applications for medical device clinical trials under the interim order: Overview. This guidance document will be updated, including by providing guidance on records retention. Guidance on the implementation of the Interim Orders for clinical trials of COVID-19 drugs is outlined in Health Canada’s Guidance on applications for drug clinical trials under the interim order: Overview. This guidance document has been updated.

Health Canada has expedited the review of COVID-19 clinical trial applications submitted under the Interim Orders with a performance standard of 14 days. As long as the need for clinical trials for drugs and medical devices used in the diagnosis, treatment, mitigation, or prevention of COVID-19 or COVID-19 complications persist, Health Canada may continue to expedite the review of clinical trial applications submitted under the Regulations.

Compliance and enforcement provisions under the FDA will continue to apply to the Regulations. As with all clinical trials conducted in Canada, Health Canada will monitor the safety of the drugs and medical devices used under the Regulations and will take immediate action, including the suspension or revocation of authorizations, if required to protect the health and safety of Canadians. Health Canada’s Compliance and Enforcement Policy (POL-0001) describes Health Canada’s national compliance and enforcement approach for health products regulated under the FDA and its regulations.

Health Canada will monitor the compliance of clinical trials with the Regulations using existing measures such as routine inspections, for-cause inspections (inspections in response to a suspected non-compliance with the regulations) and compliance verifications. The selection of COVID-19 clinical trials for an inspection will continue based on the risk to the safety and rights of participants and on the risk to the integrity of the data generated. The objectives for the inspection of human clinical trials is to verify

• adherence to generally accepted principles of good clinical practices;
• the quality and integrity of the data generated; and
• compliance with the FDA and its associated regulations.

Existing enforcement responses will apply to persons failing to comply with the FDA or the Regulations. For example, Health Canada may suspend or revoke an authorization to address non-compliance with the FDA and the Regulations. Other available enforcement responses include product seizure, investigations and prosecution.

Contact

Bruno Rodrigue Executive Director Office of Legislative and Regulatory Modernization Policy, Planning and International Affairs Directorate Health Products and Food Branch Health Canada Holland Cross, Suite P2108 11 Holland Avenue Ottawa, Ontario K1A 0K9 Address locator: 3000A Email: lrm.consultations-mlr@hc-sc.gc.ca

Footnotes

Footnote a

S.C. 2021, c. 7, s. 9

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Footnote b

R.S., c. F-27

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Footnote c

S.C. 2018, c. 27, s. 199

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Footnote d

R.S., c. P-4

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Footnote 1

SOR/2017-165

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Footnote 2

SOR/2021-199

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Footnote 3

C.R.C., c. 870

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Footnote 4

SOR/2003-196

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Footnote 5

Fall Economic Statement 2018, (ARCHIVED) Chapter 3, Take Immediate Action to Respond to Business Recommendations

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Footnote 6

According to COVID-19 data found on Statista’s website.

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Footnote 7

The MDR already has the ability to cancel the authorization in whole or in part, but not the suspension, Part 3 par. 85.2(b).

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Footnote 8

National Advisory Committee on Immunization (NACI). (ARCHIVED) Preliminary guidance on key populations for early COVID-19 immunization (2020).

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Footnote 9

Ontario Chamber of Commerce. The She-covery Project: Confronting the Gendered Economic Impacts of COVID-19 in Ontario (PDF).

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Footnote 10

Bains, Camille. Homeless vulnerable to COVID-19 need help from governments: advocates. The Canadian Press (2020).

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Footnote 11

Public Health Agency of Canada. Coronavirus Disease (COVID-19) Vulnerable Populations and COVID-19 (PDF).

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Footnote 12

Banning, Jolene. Why Indigenous communities seeing few cases of COVID-19. Canadian Medical Association Journal (2020).

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Footnote 13

Government of Canada, Infobase Canada. COVID-19 daily epidemiology update.

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