Canada
Canada
United Kingdom
United Kingdom

Quick facts

English or French Clinical trial application language English
Yes Regulatory authority & ethics committee review may be conducted at the same time Yes
No Clinical trial registration required Yes
Yes In-country sponsor presence/representation required Yes
Under 18 or 19, determined by province or territory Age of minors Under 16
Yes Specimens export allowed Yes

Regulatory Authority > Regulatory Authority

Last content review/update: August 11, 2022

Health Canada

As per the CanadaFDA, the CanadaFDR, the G-CanadaCTApps, and CAN-29, Health Canada (HC) is the competent authority responsible for clinical trial approvals, oversight, and inspections in Canada. The G-CanadaCTApps states that the HC grants permission for clinical trials to be conducted in the country, and regulates the sale and importation of drugs for use in clinical trials in accordance with the CanadaFDR provisions.

As per CAN-29, HC is one (1) of five (5) federal agencies within Canada’s “Health Portfolio” overseen by the Minister of Health. Per CAN-31, HC assesses clinical trial protocols to evaluate participant protection and safety; reviews drug quality; assures institutional ethics committee review; verifies principal investigator qualifications; and monitors and reviews adverse drug reactions. As delineated in CAN-23, HC’s Health Products and Food Branch (HPFB) is the national authority that regulates, evaluates, and monitors therapeutic and diagnostic product safety, efficacy, and quality, and reviews the information submitted in the clinical trial application.

Per CAN-16, HPFB’s activities are carried out by nine (9) Directorates and one (1) office, including the Pharmaceutical Drugs Directorate (PDD) and the Biologic and Radiopharmaceutical Drugs Directorate (BRDD). Per CAN-18 and CAN-17, the PDD and the BRDD, respectively, regulate pharmaceutical drugs, and biological drugs and radiopharmaceuticals for human use. In addition, the G-CanadaCTApps indicates that the PDD’s Office of Clinical Trials (OCT) and the BRDD’s Office of Regulatory Affairs (ORA), among others, are directly involved with the clinical trial review and approval process for pharmaceutical, biological, and radiopharmaceutical drugs. Per the G-MDSA, the Therapeutic Products Classification Committee (TPCC) may be consulted when it is not clear whether a product should be classified as a drug or device. The committee makes recommendations on the classification of a product as either a drug, medical device, or combination product. If a product does not readily meet one (1) of the statutory definitions, other regulatory areas of HC are asked to participate in the committee's discussion.

As per CAN-41, Health Canada has established a regulatory innovation agenda, which aims to provide more regulatory flexibility to support innovative research and health product development. For more details, see CAN-41.

Contact Information

According to the G-DrugApp and CAN-18, Health Canada PDD contact information is as follows:

Office of Clinical Trials
Drug Clinical Trials
Pharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Address Locator: 3105A
Ottawa, Ontario

Phone: 613-957-0368
Fax: 613-952-7756
General Inquiries E-mail:
pharma_drug_enquiries-renseignements_medicaments_pharma@hc-sc.gc.ca
Office of Clinical Trials Inquiries:
oct.enquiries-requetes.bec@hc-sc.gc.ca

Per CAN-17, the following is the contact information for biologic clinical trials:

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Building 6, Address Locator: 0601B
100 Eglantine Driveway
Tunney’s Pasture
Ottawa, Ontario
Canada K1A 0K9

Phone: 613-863-8405
General Enquiries E-mail:
hc.brdd.dgo.enquiries.sc@canada.ca

Part II (Section 30 (1.2))
Part C (Division 5 (C.05.001, C.05.002, C.05.005, and C.05.006))
1.2, 1.4, 2.1, and Appendix 1
Where to send drug submission applications
5
What is the Health Products and Food Branch?
Our Regulatory Innovation Agenda
Last content review/update: February 24, 2022

Overview

As per the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in the United Kingdom (UK). The MHRA grants permission for clinical trials to be conducted in the UK in accordance with the MHCTR and the MHCTR2006.

According to GBR-57, the MHRA is an executive agency within the Department of Health and Social Care (DHSC). MHRA’s responsibilities are to:

  • Ensure that medicines, medical devices, and blood components for transfusion meet applicable standards of safety, quality, and efficacy.
  • Ensure that the supply chain for medicines, medical devices, and blood components is safe and secure.
  • Promote international standardization and harmonization to assure the effectiveness and safety of biological medicines.
  • Help to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices, and blood components.
  • Support innovation and research and development that is beneficial to public health.
  • Influence UK and international regulatory frameworks so that they are risk-proportionate and effective at protecting public health.

Per the G-CTAuth, the agency’s Clinical Trials Unit (CTU) focuses specifically on reviewing applications to conduct clinical trials of medicinal products.

Pursuant to the MMDAct, the Secretary of State for DHSC is authorized to make clinical trials regulations and amend or supplement the law relating to human medicines, taking into consideration the safety of human medicines, the availability of human medicines, and the likelihood of the UK being seen as a favorable place to carry out research relating to human medicines, conduct clinical trials, or manufacture or supply human medicines.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Contact Information

Per GBR-58, the following is the MHRA’s contact information:

Medicines and Healthcare Products Regulatory Agency
10 South Colonnade
Canary Wharf
LONDON
E14 4PU
UK

Phone: +44 020-3080-6000
Fax: +44 0203-118-9803
General Email:
info@mhra.gov.uk
Data Protection Email:
DataProtection@mhra.gov.uk
Importing Investigational Products from Approval Countries Email:
gmpinspectorate@mhra.gov.uk

Clinical Research Office:
Email:
clintrialhelpline@mhra.gov.uk
Phone: +44 020-3080-6456

In addition, the G-CTAuth includes other email addresses for specific purposes related to submissions.

Clinical Trials Named Contact and Urgent Safety Measures
Part 1(4) and Part 3 (12, 17, and 18)
Amendment of Schedule 1 to the Principal Regulations (27 - Part 2, Conditions Based on Article 3 of the Directive)
Part 2 (Chapter 1)
Our Responsibilities
Enquiries about new guidance and procedures in place since 1 January 2021, Clinical trials of medicines, and Data protection

Regulatory Authority > Scope of Assessment

Last content review/update: August 11, 2022

Overview

In accordance with the CanadaFDA, Health Canada (HC) reviews, evaluates, and approves applications for clinical trials using authorized therapeutic products. HC also approves the sale or importation of drugs for use in clinical trials. (See the Manufacturing & Import section for additional information on importation.) As delineated in the CanadaFDR and the G-CanadaCTApps, institutional ethics committee (EC) review is required for each clinical trial site and may occur in parallel with HC’s clinical trial application (CTA) review and approval. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. See CAN-23 and CAN-19 for background information on HC’s scope of assessment.

Per the CanadaFDA, a “therapeutic product” is defined as a drug or device, or any combination of drugs and devices, but does not include natural health products; “therapeutic product authorization” refers to a license that is approved for the import, sale, advertisement, manufacture, preparation, preservation, packaging, labeling, storage, or testing of a therapeutic product. As per the G-CanadaCTApps, HC’s scope of assessment includes clinical trials (Phases I - III) using:

  • Drugs not authorized for sale in Canada in development and in comparative bioavailability studies, and
  • Marketed drugs where the proposed use of the drug for one (1) of the following is different: indication(s) and clinical use; target patient populations(s); route(s) of administration; or dosage regimen(s)

Clinical Trial Review Process

As set forth in the G-CanadaCTApps and CAN-23, HC’s Health Products and Food Branch (HPFB) coordinates the CTA approval process. The G-CanadaCTApps and CAN-23 state that prior to initiating the trial, the sponsor must file a CTA to the appropriate HPFB Directorate. CTAs involving pharmaceutical drugs should be sent to the Pharmaceutical Drugs Directorate (PDD), and CTAs involving biologics and/or radiopharmaceuticals should be sent to the Biologic and Radiopharmaceutical Drugs Directorate (BRDD).

The G-CanadaCTApps and CAN-23 indicate that upon receipt of a CTA, the HPFB Directorate (PDD/BRDD) screens the application package for completeness. If deficiencies are found, the Directorate sends the sponsor a Request for Clarification or a Screening Rejection Letter. If the Directorate finds the application complete, an acknowledgement letter is issued to indicate the 30-day default review period commenced on the date of receipt.

Per the G-CanadaCTApps, once a clinical trial is authorized, the sponsor is allowed to sell or import a drug for use in a trial, if a CTA has been filed with HC and has not received an objection within 30 days. As delineated in the G-CanadaCTApps and CAN-23, if the clinical trial is authorized, a No Objection Letter (NOL) is issued. If the CTA is rejected, a Not Satisfactory Notice (NSN) is issued. As specified in the G-CanadaCTApps and CAN-23, during the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. Please see the G-CanadaCTApps for special requirements regarding reviews of comparative bioavailability studies and joint reviews of clinical trials covering a combination of devices, biologics, and pharmaceuticals. See the Submission Process section for detailed application submission requirements.

Per the G-CanadaCTApps, soon after HC issues an NOL, it will publish the following information about the clinical trial in HC’s publicly accessible database:

  • Protocol number
  • Protocol title
  • Drug name
  • Medical condition
  • Study population
  • Authorization date
  • Sponsor name
  • HC control number
  • Trial start and end dates, if known
2 and Part II (Section 30 (1.2))
Part C (Division 5 (C.05.001, C.05.002, C.05.005, and C.05.006))
1.2, 2.1, 2.3, 2.7, and Appendix 1
5.1, 5.2, 5.5, and 5.6
Clinical Trial Site Information form
What is the Health Products and Food Branch?
Last content review/update: February 24, 2022

Overview

In accordance with the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The MPHFR and the G-CTApp specify that the scope of the MHRA’s assessment includes all clinical trials (Phases I-IV). Per G-CTApp and G-IRASCombRev, as of January 1, 2022, all new clinical trials applications must be prepared, submitted, and reviewed via the new combined review process (formerly known as Combined Ways of Working (CWoW), which offers a single application route and coordinated review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Brexit

Per the G-MHRASubmiss, Brexit, the EUCouncil-Brexit, the WithdrlAgrmt, and the G-AfterTransition, the UK withdrew from the European Union (EU) on January 31, 2020. The MHRA has updated and published clinical trials guidance that became effective on January 1, 2021; these guidance documents are referenced and described throughout this profile. G-AfterTransition summarizes the guidance to sponsors and researchers from January 1, 2021. Furthermore, the G-MHRASubmiss describes how to make certain regulatory submissions to the MHRA starting on January 1, 2021 (substantial amendments, end-of-trial notifications and developmental safety update reports (DSURs)). Per the MHCTR-EUExit and as explained in GBR-115, the new guidance went into force via the MHCTR-EUExit (also known as the "Exit Regulations"). The Exit Regulations also update existing UK legislation by, for example, replacing references to EU databases with newly established UK databases. The G-IPsNIreland delineates that the supply and use of investigational products (IPs) in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119. For broader information and a comprehensive Brexit “checker” of new rules in the UK, see GBR-60.

To help ensure the continuity of supply of IPs for clinical trials from January 1, 2021, the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain EU regulatory processes for a time-limited period. This recognition is known as “standstill.”

Per GBR-54 and GBR-86, the EU Clinical Trials Regulation (GBR-21) took effect on January 31, 2022, and the supporting online platform went live (GBR-121). GBR-115 indicates that the UK is committed to being as aligned as possible with GBR-21. The MMDAct grants authority for regulations to be made that correspond or are similar to GBR-21.

Regarding licensing of biosimilars (i.e., generic biotech medicines), see the G-Biosimilars for details on UK’s recent regulatory changes to ease or remove clinical trial requirements for the approval of biosimilars.

Clinical Trial Review Process

Application Submission

The MHCTR and the G-CTApp specify that the MHRA coordinates the clinical trial application process. Per G-CTApp and G-IRASCombRev, as of January 1, 2022, all new clinical trials applications must be prepared, submitted, and reviewed via the new combined review process (formerly known as Combined Ways of Working (CWoW). Combined review offers a single application route and coordinated review from the MHRA and the EC leading to a single UK decision for clinical trials. For support and getting started, users should review GBR-72 and contact the combined review team at cwow@hra.nhs.uk. Step-by-step instructions are provided in G-IRASCombRev. Per GBR-122 and GBR-118, ongoing trials will be migrated to the new combined review part of the Integrated Research Application System (IRAS) (GBR-78) system later in 2022. For existing trials that were approved via the standard process, amendments should continue to be submitted as per the pre-existing process. Several amendments will need to be made via the combined review process once all ongoing trials have been migrated to the new part of IRAS. See GBR-122 for additional details on the migration of existing materials in IRAS. (See Submission Process section for details on the combined review submission process.)

Other regulatory information aside from new clinical trial applications are to be submitted pursuant to the G-MHRASubmiss. These submittals include substantial amendments for existing clinical trials, end-of-trial notifications, and developmental safety update reports (DSURs). The G-CTAuth also states that clinical trials not approved or yet transitioned over to the combined review process, should continue to use the MHRA Submissions portal (GBR-13). The steps for gaining access to the MHRA Submissions portal (GBR-13) are contained in the G-MHRASubmiss and GBR-11.

For overviews of submittals to MHRA, see GBR-18 and GBR-17. (See Submission Process section for additional details.)

The G-CTApp states that the MHRA only uses automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or his/her designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered as authorized. (See the Timeline of Review section for additional details.)

In addition, as stated in the G-CTApp, certain first-in-human (Phase I) trials with specific risk factors may require the MHRA’s Clinical Trials Unit (CTU) to seek advice from an Expert Advisory Group/the Commission on Human Medicines before giving approval. See the G-CTApp for examples of which trials require expert advice and for detailed requirements.

Governance Approval

Per GBR-78, all project-based research must also apply for governance and legal compliance approvals from the appropriate lead UK Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see GBR-29.

(See the Submission Process and Submission Content sections for detailed submission requirements.)

Introduction and Article 1
When a clinical trial authorization (CTA) is needed, Trial Sponsor and legal Representative, Registration of your clinical trial, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, and Assessment of your submission
Amending your trial protocol or other documentation
Part 1 (2), Part 2 (5, 6, and 7), Part 3 (12, 14, 15, 17, and 18), and Schedule 2
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
Part 2 (Chapter 1)
Schedule 2 (Part 1(1))
Part 4 (Article 126)
Combined Review
3
6
Help (Preparing and Submitting Applications)

Regulatory Authority > Regulatory Fees

Last content review/update: August 11, 2022

According to CAN-33, there are no fees to submit a clinical trial application in Canada.

Question 5
Last content review/update: February 24, 2022

Overview

As per the MHCTR, the MHCTR2006, the G-CTApp, and the G-MHRAFees, the sponsor or his/her designated representative is responsible for paying a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) to submit a clinical trial application for authorization. According to the G-MHRAPaymt, applicants will receive an invoice to make a payment for the outstanding amount after validation of the application. Applicants must pay invoices upon receipt or they will incur penalty fees.

As delineated in the G-MHRAFees, the MHRA levies the following clinical trial processing fees, which will remain in effect through 2022:

  • 3,060 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier
  • 225 British Pounds – Applications without an IMP dossier
  • 225 British Pounds – Clinical trial variation/amendment
  • No cost – Phase IV notification

The G-CTApp further indicates that no fees are required for applications submitted and authorized under the Notification Scheme. However, if the MHRA raises an objection to the notification, the submission is treated as a standard request for authorization and an assessment of the submission is carried out with associated fees.

Instructions for Payment of Clinical Trial Application Fees

According to the G-MHRAPaymt, MHRA does not accept checks. Payments can be made electronically by bank transfer, credit card, or debit card. Bank transfers should be sent to:

Account Name: MHRA
Account Number: 10004386
Sort code: 60-70-80
Swift code: NWBKGB2L
IBAN: GB68NWBK60708010004386
Bank: National Westminster Bank

Bank address:
National Westminster Bank RBS
London Corporate Service Centre, 2nd Floor
280 Bishopsgate
London
EC2M 4RB
UK

Credit or debit card payments may be made using MHRA’s online payments service (GBR-26) referred to as “GOV.UK Pay” in the G-MHRAPaymt.

Remittance advice notices can be sent to sales.invoices@mhra.gov.uk and should include the relevant invoice number on the remittance advice. MHRA cannot accept any documentation sent by postal mail service. Further information can be obtained by emailing sales.invoices@mhra.gov.uk. G-MHRAPaymt further provides that invoice disputes/queries should be emailed to Clinical Trial Applications (CTA invoices) at ctdhelpline@mhra.gov.uk and cc: sales.invoices@mhra.gov.uk.

Fees
8 (Clinical trials
Part 3 (17)
11, 13, and Explanatory Note

Ethics Committee > Ethics Committee

Last content review/update: August 11, 2022

Overview

As indicated in the CanadaFDR and the G-CanadaCTApps, Canada has a decentralized process for the ethical review of clinical trial applications, and requires the sponsor to obtain institutional ethics committee (EC) approval for each participating trial site. (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information.

Per CAN-35 and CAN-13, institutions specifically funded by HC or the Public Health Agency of Canada (PHAC) must obtain approval from a joint EC representing those two (2) agencies—as well as complying with the CanadaFDR and the CA-ICH-GCPs. This joint EC is the HC-PHAC REB, which must review and approve all human research studies carried out by, performed by, or otherwise under the auspices of HC or PHAC. Further, if an institution is conducting an HC- or PHAC-funded project, the HC-PHAC REB must review and approve the research even if it has been previously reviewed and approved by another EC. See CAN-35 for details on the HC-PHAC REB’s development, responsibilities, and composition.

HC’s operational policy (CAN-13) outlines policies and procedures that the joint HC-PHAC REB must follow when reviewing clinical trials.

Institutional ECs are required to comply with the provisions delineated in the CanadaFDR, the G-CanadaCTApps, and the CA-ICH-GCPs. See HCNotice-CA-ICH-GCPs for more information on Canada’s implementation of the CA-ICH-GCPs. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. In addition, institutional ECs are guided by the G-TCPS2. The G-TCPS2 is an ethics policy jointly developed by Canada’s three (3) federal research agencies: the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Social Sciences and Humanities Research Council (SSHRC). Per the G-TCPS2, the G-TCPS2 sets the ethical benchmark for all Canadian institutional ECs. However, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guideline as a condition of funding. According to CAN-14, the CIHR, the NSERC, and the SSHRC created the Panel on Research Ethics (PRE) to promote the ethical conduct of research involving human participants. The PRE develops, interprets, and implements the G-TCPS2.

Ethics Committee Composition

As delineated in the CanadaFDR, the G-CanadaCTApps, and the CA-ICH-GCPs, institutional ECs must have at least five (5) members representing a mixed gender composition, the majority of which are Canadian citizens or permanent residents, and must include:

  • Two (2) members from a scientific discipline, with broad experience in the relevant research methods and areas, one (1) of whom is from a medical or dental discipline
  • One (1) member knowledgeable in ethics
  • One (1) member knowledgeable in relevant Canadian biomedical research laws
  • One (1) member from a nonscientific discipline
  • One (1) community representative

The G-TCPS2 mirrors these EC composition requirements. As mentioned earlier, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guidance as a condition of funding.

Terms of Reference, Review Procedures, and Meeting Schedule

According to the CA-ICH-GCPs, institutional ECs must establish written standard operating procedures (SOPs) to cover the entire review process. The SOPs should include EC composition, meeting schedules, notifications, frequency of reviews, protocol deviations, reporting to the EC, and recordkeeping. Further, ECs should make decisions at announced meetings where a quorum is present. Only those members who participate in the EC review and discussion should vote, provide their opinion, or advise. For detailed EC procedures and information on other administrative processes, see the CA-ICH-GCPs. In addition, for examples of EC SOPs, see CAN-13 for the HC-PHAC REB operational policy.

Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11
Part C (Division 5 (C.05.001, C.05.002, C.05.005, C.05.006, and C.05.010))
1.2, 1.4, 2.1, and 2.7
5.1, 5.2, 5.5, 5.6, and 5.10
Introduction and Chapter 6 (Articles 6.4 and 6.10)
2 and 3
About the REB and Policies, Guidelines, and Resources
Last content review/update: February 24, 2022

Overview

As set forth in GAfREC, the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), (known as research ethics committees (RECs) in the UK. ECs are part of an accountable and independent Research Ethics Service (RES) (GBR-62) to protect the dignity, rights, safety, and wellbeing of people who take part in research. ECs are authorized and recognized by the United Kingdom Ethics Committee Authority (UKECA). Also see GBR-64 for definitions of authorized and recognized ECs.

As stated in GAfREC, the RES encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Directorates (SGHSC), the Welsh Government’s Department of Health and Social Care as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the head office of the RES in England, within the Health Research Authority (HRA), to perform some UK-wide functions on behalf of the other head offices. See GAfREC for more detail about HRA functions related to the RES in the UK. A list of recognized ECs within the RES is available through GBR-95 and GBR-111.

All recognized RES ECs are required to comply with the provisions delineated in GAfREC, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9. However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. In accordance with the MHCTR and the MHCTR2006, ECs recognized to conduct reviews of clinical trials for investigational medicinal products (CTIMPs) are authorized by the statutory body, the UKECA. Please refer to the Authorizing Body section for additional details on the RES and the UKECA.

Ethics Committee Composition

As delineated in the MHCTR and GAfREC, a RES-recognized EC, which includes those recognized by UKECA, may consist of up to 18 members. Collectively, members must encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. The ECs should include a diverse mixture of members in terms of age, disability, gender, race, religion, and sexual orientation. One third of the committee must also be lay members, and half of the lay members must be persons who are not and never have been health care professionals, clinical researchers, or managers of clinical research (also known as lay members). Additionally, GAfREC states that a quorate meeting must be attended by at least seven (7) members and include the chair, at least one (1) expert member, and one (1) lay member. GBR-9 mirrors this requirement, but adds that when investigational products are reviewed, a lay member must be present. See GBR-113 for additional recommendations for composition.

Per GBR-9, in order to accommodate the United States’ (US) quorum definition pursuant to regulations for the protection of human subjects in research (45 CFR 46) and the Common Rule (45 CFR 46 Subpart A), the RES also makes special arrangements to review UK-based research funded by US Federal Government departments and their agencies. In such cases, the quorum is a majority of the EC. See the ClinRegs United States page, Ethics Committee topic for more information on ethics review requirements in the US.

As indicated in GAfREC, committee member appointments are valid for up to five (5) years. Appointments may be renewed; however, members should not normally serve more than two (2) consecutive terms of five (5) years on the same EC, and members may resign at any time. Members must maintain confidentiality regarding all ethical review related matters and refuse any projects in which they have a conflict of interest. See the MHCTR and GAfREC for additional EC composition requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

In addition to complying with composition requirements, GAfREC, GBR-113, and GBR-9 state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting. For detailed EC procedures and information on other administrative processes, see GAfREC, GBR-113, and GBR-9. Also see GBR-8 for a summary of changes to GBR-9.

1-6, Glossary, Annex C, Annex E, and Annex F
Part 2, Part 3 (11, 12, 14, 15, 17, and 18), and Schedule 2
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
Search Research Ethics Committee
Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11
Definitions of Authorised REC and Recognized REC
Introduction (Purpose and Scope, and Implementation), Terminology (Glossary), and Sections 1, 2, and 3
Selecting your REC

Ethics Committee > Scope of Review

Last content review/update: August 11, 2022

Overview

According to the CanadaFDR, the G-CanadaCTApps, the G-TCPS2, and the CA-ICH-GCPs, the primary scope of information assessed by institutional ethics committees (ECs) (called Research Ethics Boards (REBs) in Canada) relates to maintaining and protecting the dignity and rights of human research participants and ensuring their safety throughout their participation in a clinical trial. ECs must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations.) Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

The CA-ICH-GCPs also state that ECs must ensure an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants, and they must verify the adequacy of confidentiality and privacy safeguards. See the CA-ICH-GCPs for detailed ethical review guidelines.

Role in Clinical Trial Approval Process

As per the CanadaFDR and the CA-ICH-GCPs, HC must approve a clinical trial application (CTA) and an institutional EC(s) must give ethical clearance prior to a sponsor initiating a clinical trial. In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, institutional EC review for each clinical trial site may occur in parallel with HC’s CTA review and approval. Once HC completes its review, the department issues a No Objection Letter (NOL) if the CTA is approved. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until he/she submits an institutional EC approval for each participating trial site. The sponsor should use the Clinical Trial Site Information Form (see CAN-6) to submit the required information. The CanadaFDR also states that the EC must review and approve any protocol amendments prior to those changes being implemented. For HC’s interpretation of the relevant provisions of CanadaFDR, see the G-FDR-0100.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires ECs to have procedures in place to receive and respond to reports of new information, including, but not limited to, safety data, unanticipated issues, and newly discovered risks. In addition, see TCPS2-InterpReview for the Panel on Research Ethics (PRE)’s interpretations of the G-TCPS2, including on the EC’s review of secondary use of non-identifiable information, delegated review of minimal risk studies, and ongoing review.

Per CAN-8, an attestation must be completed by the EC that reviewed and approved the clinical trial. The completed attestation must be retained by the clinical trial sponsor for a period of 15 years. The attestation should not be submitted to HC unless requested. (See the Submission Process section for detailed submission requirements.)

The G-TCPS2 directs the researcher to submit an annual report to enable the EC to evaluate the continued ethical acceptability of the research. Per the G-CanadaCTApps, in the event that an EC terminates or suspends any prior approval or favorable opinion, it must document its views in writing, clearly identifying the trial, the documents reviewed, and the date for the termination or suspension.

Foreword, 1.27, 2, and 3
Part C (Division 5 (C.05.001, C.05.005, C.05.006, and C.05.010))
1.2, 1.4, 2.1, 2.5, and 2.7
5.1, 5.2, 5.5, 5.6, and 5.10
Introduction, and Chapters 1, 6, and 11
Last content review/update: February 24, 2022

Overview

According to GAfREC, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, the primary scope of information assessed by ethics committees (ECs) within the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) (GBR-62) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK). GAfREC specifies that ethical review is required for research proposals that involve investigational products (IPs), material consisting of human cells, and other situations that are described in GAfREC.

As per GAfREC, the MHCTR, the MHCTR2006, the MHCTR2006-No2, and GBR-113, ECs must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

As indicated in GAfREC, the MHCTR, the MHCTR2006, GBR-113, and GBR-9, ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See GAfREC, the MHCTR, the MHCTR2006, and GBR-9 for detailed ethics review guidelines.

Role in Clinical Trial Approval Process

As described in GBR-9, GBR-66, and GBR-95, the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. Per GAfREC and GBR-9, ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA) to conduct reviews of clinical trials for IPs (known as clinical trials for investigational medicinal products (CTIMPs) in the UK). Per GAfREC, RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than IP clinical trials. Also see GBR-64 for definitions of EC terminology and GBR-111 for a list of ECs within the RES.

As indicated in the MHCTR, the MHCTR2006, and GAfREC, IP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or his/her designated legal representative initiating the trial. The G-CTApp states that as of January 1, 2022, all new clinical trial applications must be prepared, submitted and, reviewed via the combined review process (formerly known as Combined Ways of Working (CWoW), wherein a single application route and coordinated review by MHRA and the EC leads to a single UK decision. New clinical trial applications for combined review are prepared and electronically submitted to the new combined review section of Integrated Research Application System (IRAS) (GBR-78). Per GBR-78, IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies.

According to GBR-9, the chief investigator (CI) must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the NHS REC’s Online Booking Service (GBR-95). (See the Initiation, Agreements & Registration section for additional information.)

According to the MHCTR, GAfREC, and GBR-9, for all studies, the RES requires the CI to obtain only one (1) EC review (referred to as the “main EC”) for a project taking place in the UK, regardless of the number of sites. Furthermore, GBR-9 states that the CI should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. The ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

Per GBR-68, unless an application is being processed under the proportionate review service, the applicant should attend the EC meeting if possible. The EC will notify the sponsor of its decision, usually within 10 working days of the EC meeting, and will make one (1) of the following decisions:

  • Favorable opinion
  • Favorable opinion with additional conditions
  • Provisional opinion
  • Unfavorable opinion

The MHCTR, GBR-9, and GBR-68 state that the EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion and may make one (1) written request for further information, clarification, or changes to documentation. The time required for the EC to receive a complete response to its request does not count against the 60-day timeline. Certain studies, including gene therapy studies, will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR. (See the Submission Process and Timeline of Review sections for detailed submission process requirements.)

Per GBR-116, the Health Research Authority (HRA), on behalf of the UK, is offering a new fast-track research ethics review. It is available to global clinical trials and phase I trials (commercial or non-commercial), including clinical trials of an IPs led from UK with at least one (1) other country participating; any foreign-led IP clinical trial where the UK is competing for participation; and any phase I or phase I/II IP in healthy participants. The following are not eligible for fast-track review: any clinical trial of an IP involving gene therapy, any clinical trial of an IP with funding from the US Department of Health and Human Services, and any other type of clinical trial. The fast-track EC accepts applications submitted through the new combined review section on IRAS (GBR-78). For help with fast-track ethics review within combined review, contact the fast-track team by emailing: fasttrack.rec@hra.nhs.uk.

Per GBR-9, the EC’s favorable ethical opinion applies for the stated duration of the study, except where action is taken to suspend or terminate the opinion. The MHCTR, GAfREC, and IRAS (GBR-78) require the applicant to identify an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment. See GBR-98 for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA. GBR-9 states that while the EC is not responsible for proactive monitoring, it has a duty to keep the favorable ethical opinion under review in the light of progress reports and significant developments and may review the opinion at any time. If information raises concerns about the suitability of the site or investigator, the favorable opinion may be reviewed.

Combined review of clinical trials of investigational medicinal products
2.3, 3, 4.3, and 5.4
Part 1 (2 and 3), Part 3 (11, 12, 14, 15, 17, and 18), Schedule 2, and Schedule 3 (Part 1)
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
Amendment of the Clinical Trials Regulations; Amendment of the Adults with Incapacity (Scotland) Act 2000
Search Research Ethics Committee
Foreword, 1.27, 2, and 3
Introduction (Purpose and Scope), Terminology (Glossary), and Sections 1, 3, 5, and 10.9

Ethics Committee > Ethics Committee Fees

Last content review/update: August 11, 2022

Institutional ethics committees (ECs) may independently decide whether to charge fees to conduct protocol reviews. For example, an institutional EC may require industry sponsors or other for-profit organizations to pay a fee. See specific examples of institutional fee requirements in CAN-3 and CAN-1.

Last content review/update: February 24, 2022

Overview

As set forth in GAfREC, ethics committees (ECs) are not permitted to charge an application fee or seek any other financial contribution or donation for reviewing research proposals. Additionally, EC members receive no payment for contributing to the application review process at scheduled meetings or for attending these meetings.

4.3

Ethics Committee > Oversight of Ethics Committees

Last content review/update: August 11, 2022

There are no applicable regulations or guidance regarding the registration of institutional ethics committees (ECs).

Last content review/update: February 24, 2022

Overview

Research Ethics Service

As stated in GAfREC, the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) (GBR-62) encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Directorates (SGHSC), the Welsh Government’s Department of Health and Social Care, as well as authorized ethics committees (ECs) (known as research ethics committees (RECs) in the UK). The UK Health Departments have authorized the Health Research Authority (HRA), which is sponsored by England’s DHSC, to serve as the lead administrative body to coordinate the development of RES operational systems for ECs recognized or established by the United Kingdom Ethics Committee Authority (UKECA), the HRA, or the Ministers of Health Departments of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales), including their respective head offices.

A head office represents each of the health departments within the four (4) UK nations and serves as the appointing authority for the recognized ECs. Per GAfREC and GBR-62, within England’s DHSC, the HRA is the head office with appointing authority for the RES. The official RES head offices (i.e., appointing authorities) for the other nations are represented by the Health and Social Care Research and Development (HSC R&D) Division within Northern Ireland’s HSC Public Health Agency; the Chief Scientist Office (CSO) within the SGHSC; and the Ethics Service within the Health and Care Research Wales (HCRW). The head offices work together to maintain a consistent approach in operating the RES ECs.

UK Ethics Committee Authority

As set forth in the MHCTR, the MHCTR2006, and GAfREC, the UKECA is responsible for establishing, recognizing, and monitoring ECs that review applications for investigational products (IPs) (known as clinical trials of investigational medicinal products (CTIMPs) in the UK). As indicated in the MHCTR and GBR-9, the UKECA recognizes two (2) types of ECs for new IP applications:

  • Type 1: Reviews Phase 1 clinical trials of IPs taking place at any site in the UK, where the sponsor has no knowledge of any evidence that the product has effects likely to be beneficial to the participants of the trial, and the participants are healthy and not suffering from the disease or condition to which the trial relates.
  • Type 3: Reviews clinical trials of IPs taking place at any site in the UK, including first-in-person studies involving people with the target disease or condition to which the trial relates.

Per GAfREC and GBR-9, the HRA performs some UK-wide functions, including acting on behalf of UKECA. HRA’s responsibilities also include providing advice, assistance, and operational support to all UK ECs recognized by the UKECA. Also, as indicated in GBR-97, the Four Nations Policy Leads Group is tasked with acting as the UKECA, among other duties. This group works together across the four (4) nations of the UK and provides a coordinated research approvals system and consistent policy and good practice standards. The Four Nations Policy Leads Group meetings are held every two (2) months. See GBR-97 for upcoming meeting dates.

Registration, Auditing, and Accreditation

As delineated in GAfREC and GBR-9, the RES is responsible for ensuring the quality of the ECs, including the UKECA ECs, through regular monitoring, auditing, and accrediting their operations and performance.

1.3, 2.1, 2.3, 3.3, 5.4, Glossary, Annex C, Annex D, Annex E, and Annex F
Part 2, Part 3 (12), and Schedule 2
Part 2 (Conditions Based on Article 3 of the Directive)
Introduction (Purpose and Scope), Implementation, Terminology (Glossary), and Sections 1, 2, and 3

Clinical Trial Lifecycle > Submission Process

Last content review/update: August 11, 2022

Overview

In accordance with the CanadaFDR and the G-CanadaCTApps, Canada requires the sponsor to obtain clinical trial authorization from Health Canada (HC) prior to initiating the trial. The sponsor must file a clinical trial application (CTA) to the appropriate Directorate within HC’s Health Products and Food Branch (HPFB). In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, the sponsor may submit a CTA for clinical trial authorization to the HC in parallel with its submission to an institutional ethics committee (EC) (known as a Research Ethics Board (REB) in Canada) for a favorable ethical opinion. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form (CAN-6)) for each participating trial site. The HCNotice-CTSIForm indicates that the revised CTSI form improves efficiencies and supports the submission of CTAs using the electronic Common Technical Document (eCTD) format. See CAN-30 for instructions on filling out and submitting CAN-6. CAN-19 provides a full list of HC’s forms for drug-related applications and submissions. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Regulatory Submission

Per the G-CanadaCTApps, CTAs (CAN-4) should be sent directly to the appropriate HPFB Directorate for review—the Pharmaceutical Drugs Directorate (PDD) for pharmaceutical drugs or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) for biological drugs and radiopharmaceuticals. The outer label should be clearly identified with "Clinical Trial Application".

The G-MDSA and the G-CanadaCTApps indicate that sponsors may request a pre-submission/application meeting with the appropriate Directorate within HPFB if they have any questions or concerns prior to filing a CTA. Additional details on requesting a meeting and meeting procedures are available in the aforementioned guidance documents. According to CAN-4, the submission can be in French or English. For CTAs that use pharmacometric approaches, sponsors should consider the policy statements in G-Pharmacometrics. Pharmacometrics is the science of using quantitative analysis and modelling and simulation approaches to inform and enhance drug development and regulatory review.

Per the CanadaFDR, an application by a sponsor for authorization to sell or import a drug for the purposes of a clinical trial must be submitted to HC, signed and dated by the sponsor’s senior medical or scientific officer in Canada and senior executive officer. The sponsor’s clinical trial attestation must be submitted with the application (CAN-4). For guidance on completing CAN-4, see the G-DrugApp.

Per the G-CanadaCTApps, the G-MDSA, and the Non-eCTDformat, HC accepts clinical trial submissions/applications in the eCTD and non-eCTD electronic-only formats. The Non-eCTDformat indicates that the eCTD format is recommended. Per CAN-44, once a submission is filed in eCTD format, all additional information and subsequent regulatory activities for the same dossier (protocol) must be filed in eCTD format, and sponsors must not revert to non-eCTD electronic-only format.

According to the ElecSubms, CTAs in eCTD format are available upon request via email to no-reply.ereview.non-reponse@hc-sc.gc.ca; the text 'Request for Clinical Trial Applications in eCTD Format' should be in the subject line of the email. HC’s guidance documents: “Preparation of Regulatory Activities in eCTD Format” and “Common Electronic Submissions Gateway (CESG) Health Canada Reference Guide” are available upon request via email to no-reply.ereview.non-reponse@hc-sc.gc.ca; the text ‘Request for eCTD Guidance Document’ should be in the subject line of the email. Background information about CESG is available at CAN-25. Applicants must request a dossier ID from HC for eCTD dossiers. The dossier ID request forms for drug and biological product clinical trials are available via ElecSubms. A request for a dossier ID should be sent a maximum of eight (8) weeks prior to filing a clinical trial application in the eCTD format. Per CAN-44, for eCTD format, prior to filing a CTA via the CESG, each company must file a sample transaction to HC in accordance with the applicable guidance documents. Additional questions regarding the CESG and eCTD submissions may be directed to ereview@hc-sc.gc.ca.

For non-eCTD electronic submissions, based on information provided in the G-CanadaNon-eCTD and the G-MDSA, sponsors must submit CTAs on electronic media—a disc or drive. HC recommends PDF and/or MS-Word (where required) for the CTA. The PDF documents must be generated from electronic sources (not scanned material), no larger than 150 MB, properly bookmarked, hyperlinked, and organized in accordance with the CTD specifications in the G-CanadaCTApps and the G-CanadaNon-eCTD. Finally, the sponsor must include a cover letter in both electronic and paper format. (For detailed cover letter requirements, see the G-CanadaNon-eCTD). HC advises sponsors to complete the CTA using the G-CanadaCTApps in conjunction with the G-CanadaNon-eCTD. For validation rules, see the Rules-Non-eCTD. The ElecSubms contains a zip file of the folder structure for clinical trial non-eCTD submissions. The G-Canada-CTD also provides detailed CTD format/structure requirements.

Per the G-CanadaNon-eCTD, sponsors should send CTAs directly to the appropriate Directorate within HC’s HPFB in the following media formats:

  • DVD-RAM UDF standard
  • Single and dual layer Recordable Digital Versatile Discs
  • Single and dual layer Blu-ray discs
  • USB 2.0 or 3.0 drive
  • Portable External Hard Drive with USB 2.0 or 3.0 interfaces

In addition, the G-CanadaNon-eCTD indicates that media should not be password protected, and must be provided on a single disc/drive, scanned using virus-scanning software, and certified as virus free. All discs/drives should be labelled with the following information:

  • Sponsor
  • Brand Name of Drug Master File (DMF) Name
  • Dossier Identifier (if known)
  • Control Number or DMF Number (if known)
  • "Protected B"
  • "This media has been virus-scanned and we certify that it is virus free"
  • Month and year of filing

As per CAN-18 and CAN-17, non-eCTD CTAs involving pharmaceutical drugs should be sent to PDD, and CTAs involving biologics and/or radiopharmaceuticals should be sent to BRDD to the addresses listed below.

Office of Clinical Trials
Pharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Address Locator: 3105A
Ottawa, Ontario
Canada K1A 0K9
Phone: 613-957-0368
Fax: 613-952-7756

Office of Clinical Trials Inquiries: oct.enquiries-requetes.bec@hc-sc.gc.ca
General Inquiries E-mail:
pharma_drug_enquiries-renseignements_medicaments_pharma@hc-sc.gc.ca

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Building 6, Address Locator: 0601B
100 Eglantine Driveway
Tunney’s Pasture
Ottawa, Ontario
Canada K1A 0K9
Phone: 613-863-8405
General Enquiries E-mail:
hc.brdd.dgo.enquiries.sc@canada.ca

Per the HCNotice-CTSIForm, questions related to pharmaceutical CTSI forms should be sent to: oct.enquiries-requetes.bec@hc-sc.gc.ca and questions related to biologic CTSI forms should be sent to brdd.ora@hc-sc.gc.ca.

According to the G-MDSA, HC no longer accepts paper copies of CTAs, CTA amendments, and CTA notifications. See the G-CanadaNon-eCTD, the G-CanadaCTApps, and the G-Canada-CTD for detailed document preparation and submission requirements.

Ethics Review Submission

As indicated in the CanadaFDR and the G-CanadaCTApps, all research involving human participants in Canada must be reviewed by an institutional ethics committee (EC). (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements. Further, Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information. See CAN-35 for submission requirements to the joint HC-Public Health Agency of Canada (PHAC)’s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

Part C (Division 5 (C.05.002, C.05.004, C.05.005))
Guidance documents, notices, and supporting documents
2-5, and Appendix D
1.2, 2.2, 2.3, and 2.7
1-3 and Appendix D
5.2, 5.4, and 5.5
7.1, 8.1, and 8.2
1.2
Last content review/update: February 24, 2022

Overview

In accordance with the MHCTR, the MHCTR2006, the G-CTApp, and GBR-9, the United Kingdom (UK) requires the sponsor or his/her designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. Per G-CTApprovedCountries, MHCTR-EUExit lists the countries where a clinical trial sponsor or their legal representative may be established; these countries are initially European Union (EU) and European Economic Area (EEA) countries.

(See the Submission Content section for detailed submission content requirements).

Delivery Information for Clinical Trial Application

Per G-CTApp and G-IRASCombRev, as of January 1, 2022, all new clinical trials applications must be prepared, submitted, and reviewed via the new combined review process (formerly known as Combined Ways of Working (CWoW). Combined review offers a single application route and coordinated review from the MHRA and the EC leading to a single UK decision for clinical trials. For support and getting started, users should review GBR-72 and contact the combined review team at cwow@hra.nhs.uk. Step-by-step instructions are provided in G-IRASCombRev. (Note: G-IRASCombRev will be updated regularly and is evolving.) Per GBR-122 and GBR-118, ongoing trials will be migrated to the new combined review part of the Integrated Research Application System (IRAS) (GBR-78) system later in 2022. For existing trials that were approved via the standard process, amendments should continue to be submitted as per the pre-existing process. Once all ongoing trials have been migrated to the new system, several amendments will need to be made via the combined review process in the new part of IRAS. See GBR-122, for additional details on the migration of existing materials in IRAS.

GBR-72 outlines how the new combined review process is different. First, because applicants must submit to the EC and the MHRA together, not separately, combined review may require organizations to change their operations. For example, individuals can view and revise the application information in IRAS instead of generating a PDF of an in-progress application. This new feature may affect quality control processes within the system. For example, collaborators can be granted a view-only or read-write access to IRAS. Another change is that messages from the IRAS will only go to a specific set of contacts. If organizations have different teams working on different parts of the application, there must be effective internal communication mechanisms in place. IRAS messages could include Requests for Further Information (RFIs) or a final outcome issued. Finally, applicants will receive a consolidated initial outcome. If there is anything that needs to be addressed for the trial to be approved, applicants should respond within 14 days. If more time is needed to respond to an RFI, an extension can be formally requested by emailing clintrialhelpline@mhra.gov.uk and indicating how much time is needed. Under combined review, applicants receive a final decision on their application within 10 days of receipt of a response to an RFI.

Per G-IRASCombRev, to submit a new clinical trial application in the combined review section of IRAS (GBR-78), applicants must complete pre-submission procedures that includes creating an account in IRAS (if a new user), creating a new project and key roles, entering and uploading project details, and routing the application to the sponsor for their review and authorization. Once the sponsor or its delegate has authorized the submission, the chief investigator (CI) or project deputy will receive a notification to complete the EC booking. When selecting an EC meeting that is not the first available meeting, the 60-day regulatory clock for both the EC and the MHRA will start on the cut-off date for the meeting that is chosen. Once booked, the EC booking page will update to show the confirmed booking details. The CI/project deputy will then be able to scroll down the page to select the option to “submit to the regulators.” See G-IRASCombRev for detailed step-by-step instructions.

Other regulatory information aside from new clinical trial applications are to be submitted pursuant to the G-MHRASubmiss. These submittals include substantial amendments for existing clinical trials, end-of-trial notifications, and developmental safety update reports (DSURs). The G-CTAuth also states that clinical trials not approved or yet transitioned over to the combined review process should continue to use the online MHRA Submissions portal (GBR-13). The steps for gaining access to the UK portal MHRA Submissions (GBR-13) are contained in the G-MHRASubmiss and GBR-11.

For overviews of submittals to MHRA, see GBR-18 and GBR-17.

As described in GBR-78, other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the National Institute for Health Research Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

Assembly and Number of Copies

Per GBR-72, new applications must be submitted and managed using the new combined review section of IRAS (GBR-78).

Clinical Trial Application Language Requirements

As delineated in the MHCTR, the clinical trial application and accompanying material must be provided in English.

Trial Sponsor and legal Representative, Combined review of clinical trials of investigational medicinal products, and Documents to send with your application
2
Amending your trial protocol or other documentation
Part 1 (3) and Part 3 (12, 14, 17, and 18)
2
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
Combined Review
3
CI Checklist Before Seeking Approval, CTA Submission, Unique Trial Number, EudraCT Number
Help (Preparing and Submitting Applications)
Terminology (Glossary) and Sections 1.2 and 14

Clinical Trial Lifecycle > Submission Content

Last content review/update: August 11, 2022

Regulatory Authority Requirements

As set forth in the CanadaFDR, the G-CanadaCTApps, and CAN-31, Health Canada (HC) requires the sponsor to apply for clinical trial authorization by submitting a clinical trial application (CTA) to HC. As specified in the G-CanadaCTApps, the G-CanadaNon-eCTD, the G-Canada-CTD, and the G-QCM-PharmCTAs, the CTA should be organized into three (3) modules in Common Technical Document (CTD) format:

  • Module 1 - Administrative and clinical information about the proposed trial
  • Module 2 - Quality (Chemistry and Manufacturing) summaries about the drug product(s) to be used in the proposed trial
  • Module 3 - Additional supporting quality information

Per the CanadaFDR, the clinical trial application form (CAN-4) and the following information and documents must be submitted:

  • Protocol
  • Summary of potential risks/benefits
  • Clinical trial attestation that includes drug information (chemistry, names, classifications, dosage, therapeutic purpose, human-sourced excipient, drug identification number or notice of compliance, manufacturing information); sponsor’s contact information; if the drug is to be imported, contact information for the sponsor’s representative in Canada who is responsible for the sale of the drug; and contact information for the qualified investigator at each site, if known at the time of submittal
  • Contact information for each institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) that approved the protocol, if known at the time of submitting the application
  • Contact information of any institutional EC that previously refused to approve the protocol, its reasons, and refusal date
  • Investigator’s Brochure (IB)
  • Informed consent form (ICF)
  • Information about use of a human-sourced excipient
  • Chemistry and manufacturing information
  • Proposed date for trial commencement at each site, if known

Per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form CAN-6)) for each participating trial site. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Refer to the CanadaFDR, the G-CanadaNon-eCTD, the G-CanadaCTApps, the G-Canada-CTD, the G-DrugApp, and the G-QCM-PharmCTAs for detailed submission information.

Ethics Committee Requirements

Each institutional EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies to be supplied and application format requirements. However, the following requirements comply with the CA-ICH-GCPs and are basically consistent across all Canadian ECs:

  • Clinical protocol
  • ICFs and participant information
  • Participant recruitment procedures
  • IB
  • Safety information
  • Participant payments and compensation
  • Investigator(s) current curriculum vitaes (CVs)
  • Additional required institutional EC documentation

See section 3.1.2 of CA-ICH-GCPs for additional submission content requirements.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires clinical trial researchers to include a plan for monitoring safety, efficacy/effectiveness (where feasible), and validity in their proposal for EC review. See the G-TCPS2 for additional details on the plan’s required contents.

See CAN-35 for submission requirements to the joint HC-Public Health Agency of Canada (PHAC)'s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

Clinical Protocol

As delineated in the CA-ICH-GCPs, the clinical protocol should include the following elements:

  • General information
  • Background information
  • Trial objectives and purpose
  • Trial design
  • Participation selection/withdrawal
  • Participant treatment
  • Efficacy assessment
  • Safety assessment
  • Statistics
  • Direct access to source data/documents
  • Quality control/quality assurance procedures
  • Ethical considerations
  • Data handling and record keeping
  • Financing and insurance
  • Supplements

For complete protocol requirements, see section 6 of CA-ICH-GCPs.

3.1.2, 6, and 7
Apply for Ethics Review
Part C (Division 5 (C.05.001, C.05.004, and C.05.005))
2-5, and Appendix D
2.3 and 2.7
1-3 and Appendix D
5.1, 5.4, and 5.5
I, S – Drug Substance, and P – Drug Product
Chapter 11 (Article 11.6)
Last content review/update: February 24, 2022

Overview

As set forth in the MHCTR, the MHCTR2006, the G-CTApp, and GBR-9, the Medicines and Healthcare Products Regulatory Agency (MHRA) requires the sponsor or his/her designated legal representative to apply for clinical trial authorization, and the chief investigator (CI) to apply for a favorable opinion from a recognized ethics committee (EC). (See the Ethics Committee topic for detailed coverage of EC operations and responsibilities.)

Regulatory Authority Requirements

As specified in the G-CTApp, a clinical trial submission package to the MHRA should contain the following documents:

  • Cover letter (when applicable, the subject line should state that the submission is for a Phase I trial and is eligible for a shortened assessment time, or if it is submitted as part of the notification scheme); this letter should clearly highlight the Purchase Order (PO) number to help MHRA invoice and allocate payments promptly and efficiently
  • Clinical trial application form in PDF and XML versions
  • Protocol document
  • Investigator’s brochure (IB)
  • Investigational medical product dossier (IMPD) or a simplified IMPD
  • Summary of scientific advice obtained from the MHRA or any other regulatory authority, if available
  • Manufacturer’s authorization, including the importer’s authorization and Qualified Person declaration on good manufacturing practice for each manufacturing site if the product is manufactured outside the European Union (EU) (See G-ImportIMPs and the Manufacturing & Import section for more information)
  • Copy of the United Kingdom (UK) or the European Medicines Agency’s decision on the pediatric investigation plan and the opinion of the pediatric committee, if applicable
  • Content of the labelling of the investigational medicinal product (IMP) (or justification for its absence)

Per the G-PIPs, UK marketing authorization holders who sponsor a study that involves the use of the authorized medicinal product in the pediatric population, must submit to the MHRA results of the study within six (6) months after the trial ended. Additional details and submittal details are in the G-PIPs and the G-PIPsProcess.

Per the G-RiskAssmt, MHRA recommends that a risk assessment is undertaken for all clinical trials. Phase 1 trials are required to have a documented risk assessment process and to produce a risk assessment for all proposed trials. The risk assessment should be done as early as possible to help the sponsor identify whether the sponsor wishes to proceed with sponsorship and also the potential category of investigational product (IP) for eventual marketing authorization. An early risk assessment will also identify the study management requirements, which can assist in the planning and resourcing aspects of the trial (e.g., identification of trial monitoring requirements so that these can be budgeted for in any funding application). There is no requirement to submit risk assessments to the MHRA or the EC. However, any safety monitoring produced as a result of the risk assessment must be described in the protocol. Finally, information contained in the risk assessment may prove useful in completing the application form for approvals, particularly for the EC application. See the G-RiskAssmt for details on how to conduct the risk assessment.

Ethics Committee Requirements

As per the MHCTR, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), ECs require the CI to submit the following documentation for ethics approval:

  • Application for an EC opinion
  • A summary of the trial, including justification, relevance, and methodology to be used
  • Research hypothesis
  • Statistical analysis and justification for the numbers of participants to be recruited
  • Protocol
  • IB
  • Peer review process details
  • Sponsor name and contact information
  • Financial arrangements for the trial (e.g., funding sources, participant reimbursement, compensation provisions in the event of trial-related injury or death, and insurance or indemnity coverage for sponsor and investigator(s)) (See the Insurance & Compensation section for additional information)
  • Terms of agreement between sponsor and participating institution(s)
  • Material to be used (including advertisements) to recruit potential research participants
  • Informed consent form and copies of materials to be provided to participants (See the Required Elements section for additional information)
  • Participant treatment plans
  • Benefit/risk assessment for participants
  • Investigator(s) Curriculum Vitaes (CVs)
  • Trial design and suitability of facilities

See GBR-77 for a compilation of guidance for the EC form questions in the Integrated Research Application System (IRAS) (GBR-78). Further, to help with planning before seeking EC approval, GBR-18 provides a checklist for CIs.

Clinical Protocol

According to GBR-113, the clinical protocol should contain the following elements:

  • Protocol Summary
  • Sponsor or designated representative name and contact information
  • Investigator(s) CV(s) and contact information
  • IP description (See the Investigational Products topic for detailed coverage of this subject)
  • Form, dosage, route, method, and frequency of administration; treatment period
  • Trial objectives and purpose
  • Trial design, random selection method, and blinding level
  • Participant selection/withdrawal
  • Participant treatment
  • Summary of potential risks and known benefits to research participants
  • Safety and efficacy assessments
  • Adverse event reporting requirements (See the Safety Reporting section for additional information)
  • Statistics and methods to track trial data
  • Sponsor specifications for direct access to source data/documents
  • Quality control/quality assurance procedures and practices
  • Ethical considerations
  • Data management and recordkeeping
  • Financing and insurance details
  • Publication policy

For complete protocol requirements, refer to GBR-113.

Documents to send with your application
Legal Background and Scope
Part 3 (12, 14, 15, 17, and 18) and Schedule 3 (Parts 1 and 2)
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
3.1 and 6
CI Checklist Before Seeking Approval
Terminology (Glossary) and Section 14

Clinical Trial Lifecycle > Timeline of Review

Last content review/update: August 11, 2022

Overview

As delineated in the CanadaFDR and the G-CanadaCTApps, the review and approval of a clinical trial application (CTA) by Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) may be conducted in parallel. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form) for each participating trial site. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Regulatory Authority Approval

According to the CanadaFDR and the G-CanadaCTApps, an authorized clinical trial is one that has been filed with HC and has not received an objection within 30 days. All CTAs are subject to the 30-day default period from the date of receipt of the completed application at the appropriate Directorate within HC’s Health Products and Food Branch (HPFB). While the Directorates can establish shorter administrative targets of seven (7) days for the review of bioequivalence trials, the 30-day default system remains the regulatory requirement. Applications to conduct Phase I clinical trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines, or reproductive and genetic technologies are not included in the seven-day target system. Please see the G-CanadaCTApps for special requirements regarding reviews of comparative bioavailability studies and joint reviews of clinical trials covering a combination of devices, biologics, and pharmaceuticals.

As specified in the G-CanadaCTApps and the G-MDSA, during the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. The G-MDSA clarifies that, where warranted, HC can adjust the timelines to be longer or shorter based on the complexity of the request, dialogue with the sponsor, and/or circumstances of the review, including pausing the clock during the scientific review. According to the G-CanadaCTApps and the G-MDSA, if HC authorizes the CTA, then it issues a No Objection Letter (NOL). If HC rejects the CTA, it sends a Not Satisfactory Notice (NSN). HC will issue an NSN if it identifies significant deficiencies, or, if a timely response to requested information has not been provided. The sponsor may resubmit the information and material at a future time, and it will be processed as a new CTA.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. However, according to the CA-ICH-GCPs, the institutional EC should review a proposed clinical trial within a reasonable time. The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, recommends a proportionate approach to ethics review—the lower the level of risk, the lower the level of scrutiny (delegated review); the higher the level of risk, the higher the level of scrutiny (full board review). In either case, pursuant to the G-TCPS2, the institutional EC should make its decisions in an efficient and timely manner. See CAN-35 for ethics review timelines with the joint HC-Public Health Agency of Canada (PHAC)'s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

3.1.2
Part C (Division 5 (C.05.005 and C.05.006))
2.1, 2.3.3, 2.5, and 2.7
5.5 and 5.6
11.1, 12.1 and 13.3-13.4
Chapter 2 (Articles 2.8 and 2.9) and Chapter 6 (Article 6.13)
Apply for Ethics Review
Last content review/update: February 24, 2022

Overview

Based on the MHCTR, the MHCTR2006, GAfREC, and GBR-9, the sponsor or his/her designated representative must submit an application for clinical trial authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA)'s, and the chief investigator (CI) must submit an application to a recognized ethics committee (EC) to obtain a favorable opinion prior to the trial’s commencement.

Note: Per G-CTApp and G-IRASCombRev, starting from January 1, 2022, all new clinical trials applications must be prepared, submitted, and reviewed via the new combined review process (formerly known as Combined Ways of Working (CWoW). Combined review offers a single application route and co-ordinated review from the MHRA and the EC leading to a single United Kingdom (UK) decision for clinical trials. The service is available to sponsors and applicants in a new section of the Integrated Research Application System (IRAS) (GBR-78). For support and getting started, users should review GBR-72 and contact the combined review team at cwow@hra.nhs.uk. Step-by-step instructions are provided in G-IRASCombRev.

Combined Review

Per the G-CTApp, the initial combined review assessment will be completed within 30 days of being submitted. Applications for healthy volunteer trials and sponsor-determined phase I trials in non-oncology patients may qualify for a shortened assessment time and MHRA will work with the EC to expedite these applications. MHRA and the EC will inform applicants of the outcome of a submission. If there are grounds for non-acceptance of the application, the applicant will have the opportunity to respond--usually within 14 days, though this may be extended on request. Communication informing the applicant of the MHRA and EC decisions following receipt of the responses will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of the decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days receiving the original application unless otherwise advised.

The G-CTApp states that MHRA has moved from paper to automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or his/her designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

In addition, as stated in the G-CTApp, certain first-in-human (Phase I) trials of investigational products with higher risk or greater elements of uncertainty require the MHRA to seek advice from the Clinical Trials, Biologicals, and Vaccines Expert Advisory Group (CTBVEAG) of the Commission on Human Medicines before approval for the trial can be given. See the G-CTApp for detailed requirements.

Per GBR-9, the ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK. See the Scope of Review section for additional information on the “main EC.”

Combined review of clinical trials of investigational medicinal products, Assessment of your submission, and Applications that need expert advice
3
Part 2 (5 and 7), Part 3 (12, 14, 15, 17, and 18)
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
Terminology (Glossary) and Sections 1, 3, 5, and 14

Clinical Trial Lifecycle > Initiation, Agreements & Registration

Last content review/update: August 11, 2022

Overview

In accordance with the CanadaFDR and the G-CanadaCTApps, a clinical trial can only commence after the sponsor receives authorization from both Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada). No waiting period is required following the applicant’s receipt of these approvals. CAN-30 specifies that for purposes of the Clinical Trial Site Information form, the date of commencement of the trial is the date when the clinical trial site is ready to enroll participants. The commencement date is a date after which the sponsor has both the HC authorization from the appropriate Directorate (date on the No Objection Letter (NOL)) and approval from the relevant EC. Further, the commencement date would be the date when the sponsor implements the protocol, which includes the screening period that occurs prior to the check-in date. See the Scope of Review section for detailed institutional EC requirements, and the Submission Content section for additional HC approval information. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

In addition, if a sponsor (Canadian or foreign) wants to import a drug into Canada to conduct a clinical trial, he/she must include a copy of HC’s clinical trial authorization (i.e., the NOL) with the drug shipment. According to the G-CanadaCTApps and CAN-32, if a sponsor plans to import investigational drugs directly to each trial site, then the sponsor must also authorize the importer (i.e., the clinical trial site) when submitting the clinical trial application using Appendix I of HC’s Drug Submission Application Form (CAN-4). See the Manufacturing & Import section for detailed import requirements.

Clinical Trial Agreement

Prior to initiating the trial, as delineated in the G-FDR-0100 and the CA-ICH-GCPs, the sponsor must sign an agreement between all involved parties, including ECs, Qualified Investigators (QIs), contract research organizations, and others, to ensure full compliance with the regulatory requirements. Further, the sponsor should obtain the investigator’s/institution's agreement:

  • To conduct the trial in compliance with good clinical practice, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC
  • To comply with procedures for data recording and reporting
  • To permit monitoring, auditing, and inspection
  • To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

In accordance with the G-CanadaCTApps, prior to initiating a clinical trial, the sponsor must ensure that a Qualified Investigator Undertaking (QIU) form (CAN-37 or similar documentation that meets the CanadaFDR requirements) has been completed and is kept on file by the sponsor. Per the CanadaFDR, the form certifies that the QI will conduct the clinical trial in accordance with good clinical practices and will immediately inform trial participants and the institutional EC of trial discontinuance and the reason for this discontinuance. If there is a change in the QI at a site, a new CTSI Form must be submitted to HC, and a new QIU form must be maintained by the sponsor.

See CAN-6, CAN-8, and CAN-19 for additional clinical trial forms.

Clinical Trial Registration

As per the G-CanadaCTApps, sponsors should register their clinical trials on one (1) of two (2) publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization (WHO), ClinicalTrials.gov (CAN-45), and the International Standardized Randomized Controlled Trial Number (ISRCTN) Registry (CAN-46). According to HCNotice-CTRegDisc, clinical trial registration is not a mandatory requirement at this time. However, per the G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, clinical trials must be registered before recruitment of the first trial participant in a publicly accessible registry that is acceptable to the WHO or the International Committee of Medical Journal Editors (ICMJE). In addition, following registration, researchers are responsible for ensuring that the registry is updated in a timely manner with: new information; safety and, where feasible, efficacy reports; reasons for stopping a trial early; and the location of findings.

1.17, 5.1.2, 5.6.3, and 8.2.6
Part C (Division 5 (C.05.006 and C.05.012))
1.2 and 2.7
5.6 and 5.12
Chapter 11 (Articles 11.10, 11.11, and 11.17)
Last content review/update: February 24, 2022

Overview

In accordance with the MHCTR, the MHCTR2006, GAfREC, and GBR-9, a clinical trial can only commence after the sponsor or his/her designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). No waiting period is required following the applicant’s receipt of these approvals. Per the MHCTR and GBR-18, specific documentation, including MHRA licensing, must be in place before an investigational product (IP) can be released for a clinical trial.

GBR-103 provides that if a sponsor(s) is not established in the United Kingdom (UK) or on an approved country list (which initially includes European Union (EU)/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Per G-CTApprovedCountries, MHCTR-EUExit will refer to a list of countries where a sponsor of a clinical trial, or their legal representative, may be established; these countries are initially EU and EEA countries.

GBR-9 states that the CI should be based in the UK. In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

In addition, per the MHCTR and the G-CTApp, a Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)), including the importer’s authorization and qualified person declaration on good manufacturing practice for each manufacturing site if the product is manufactured outside the EU, must be obtained by the person responsible for the manufacture or importation of any IP to be used in the trial. The sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. (See the Submission Content and Manufacturing & Import sections for detailed submission and IMP requirements respectively).

As stated in the MHCTR, all investigators must possess appropriate qualifications, training, and experience. The trials should be conducted in compliance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), and laboratory practices for investigational products must comply with the UK-GLPs. Also note, GBR-101 is the United Kingdom’s (UK) policy framework that sets out principles of good practice in the management and conduct of health and social care research, and incorporates the UK’s research transparency strategy, Make It Public (GBR-55), comprising transparency in registration and reporting.

See GBR-18 for a suggested checklist of documentation that should be in place at the main site before a clinical trial begins.

Per GBR-78, all project-based research must also apply for governance and legal compliance approvals from the appropriate lead UK Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see GBR-29.

Clinical Trial Agreement

According to GBR-107 and GBR-70, contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates for industry-sponsored clinical trials with the NHS/Department of Health and Social Care (DHSC) participants in hospitals throughout the UK Health Services, which encompasses England, Northern Ireland, Scotland, and Wales. These 2021 model agreements replace the 2020 versions. See GBR-107 for the notes that provide further background, an overview of the changes from the 2020 versions, and more information on how and under which circumstances the templates should be used. While the 2020 versions of these templates will still be accepted in IRAS (GBR-78), applicants are encouraged to adopt the 2021 versions at their earliest opportunity. Versions older than March 2020 are no longer accepted with new IRAS submissions. Applicants are advised to use the templates without modification. Any proposed modifications will not be accepted unless first agreed to by the UK Contracting Leads. Proposing modifications to the templates is likely to result in significant delay. Feedback on the content of the templates and their use by sponsors should be provided to mCTA@hra.nhs.uk.

GBR-107 also provides the model non-commercial agreement (mNCA) template to meet the requirements of non-commercial sponsors and the NHS/DHSC bodies undertaking the research. This agreement has been developed as a single, UK-wide agreement template, meaning that it can be used irrespective of where the sponsor and research site are established. It is designed to be used without modification or negotiation. The mNCA has been developed for a range of interventional research scenarios, including clinical trials, medical device studies, research using patient data, and research using human tissue. The terms and conditions are suitable for all such scenarios and only the completion of highlighted sections, including the schedules of the agreement, will differ depending on the study involved.

Additional details and templates are available in GBR-107 and GBR-70.

Ethics Committee Confirmation of Review and Approval

The MHCTR and the MHCTR2006 mandate that the sponsor or his/her designated representative is responsible for ensuring that the CI has obtained confirmation of the EC’s approval. Per G-CTApp and G-IRASCombRev, as of January 1, 2022, all new clinical trials applications must be prepared, submitted, and reviewed via the new combined review process (formerly known as Combined Ways of Working (CWoW), which offers a single application route and coordinated review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

As per the MHCTR and GBR-9, the sponsor or his/her designated representative should also notify the EC of any substantial amendments to the protocol, and submit all relevant documents in support of such amendments. These amendments may not be implemented without a favorable opinion from the EC. (See the Scope of Review and Submission Content sections for additional details on the EC review and approval process).

Clinical Trial Registration

As per the GBR-102 and the G-CTApp, the sponsor or investigator is required to register the clinical trial in a publicly accessible database as a condition of a favorable ethical opinion. Registration should occur before the first participant is recruited and no later than six (6) weeks after recruitment of the first participant. To help researchers meet the UK’s transparency requirements, GBR-102 indicates that from January 1, 2022, the HRA will automatically register approved clinical trials with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (GBR-47) to ensure that information is publicly available. ISRCTN is the UK's preferred clinical trials registry. HRA’s commitment to register clinical trials on behalf of sponsors and researchers is in line with the “Make It Public” research transparency strategy (see GBR-55). Per GBR-102, HRA also recognizes any register covered by the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE), such as clinical trials.gov (GBR-49). The G-CTApp clarifies that it is still a standard condition of an EC favorable opinion for clinical trials to be registered on a publicly accessible database, and this requirement has not changed. For any submissions prior to December 31, 2021, the applicant should have registered their clinical trial on an established international register. If deferral of registration is needed, then contact the HRA at study.registration@hra.nhs.uk. The registry number(s), if available, should continue to be used in section A.5. of the application form in IRAS (GBR-78) when preparing the application. If this number is not available at the time of application, email the MHRA at clintrialhelpline@mhra.gov.uk with subject line “Clinical Trial Registration” within six (6) weeks of recruiting the first research participant. The applicant should also let the EC know the registration number as soon as possible.

Data Safety and Monitoring Board

Per GBR-18, the CI should ensure that arrangements are made for a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK). The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Registration of your clinical trial, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, and Assessment of your submission
2
3.2
Part 1 (3), Part 3 (12, 13, 14, 17, 18, 22, and 24) and Part 6 (36 and 38)
2
Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
7
1.17, 5.1.2, and 8.2.6
CI Checklist Before Seeking Approval and Final Trial Management Documentation
6
Help (Preparing and Submitting Applications)
Terminology (Glossary) and Sections 1, 3, and 14

Clinical Trial Lifecycle > Safety Reporting

Last content review/update: August 11, 2022

Safety Reporting Definitions

According to the CanadaFDR and G-CanadaCTApps, and the CA-ICH-GCPs, the following definitions provide a basis for a common understanding of Canada’s safety reporting requirements:

  • Adverse Event (AE) – Any adverse occurrence in the health of a clinical trial subject who is administered a drug that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.
  • Adverse Drug Reaction (ADR) – Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.
  • Serious Adverse Drug Reaction (SADR) or Serious Adverse Event (SAE) – Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or causes a congenital anomaly/birth defect.
  • Serious, Unexpected ADR – A serious ADR that is not identified in nature, severity, or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs), requires researchers to promptly report new information revealed during the conduct of the trial that might affect the welfare or consent of participants to the EC, to a publicly accessible registry, and to other appropriate regulatory or advisory bodies. In addition, when new information is relevant to participants’ welfare, researchers must promptly inform all participants to whom the information applies (including former participants). Researchers must work with their ECs to determine which participants must be informed, and how the information should be conveyed.

For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Safety Reporting Requirements

Investigator Responsibilities

Per the CA-ICH-GCPs, all SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify participants by unique code numbers assigned to the trial subjects rather than by their names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the EC. AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. For reported deaths, the investigator should supply the sponsor and the EC with any additional requested information (e.g., autopsy reports and terminal medical reports).

Sponsor Responsibilities

As delineated in the CanadaFDR, the G-CanadaCTApps, the HCNotice-E2A, and CAN-22, the sponsor is required to expedite reports of ADRs to HC that meet these three (3) criteria: serious, unexpected, and having a suspected causal relationship. ADR reports that are expected or unexpected, but not serious, should not be reported to HC, but rather monitored and tracked by the sponsor. Further detail and clarifications on AE/ADR reporting criteria can be found in the HCNotice-E2A and CAN-22. As specified in the G-CanadaCTApps and the HCNotice-E2A, when evaluating whether an AE is serious and unexpected, the Qualified Investigator’s (QI) and sponsor’s determination of causality is important. Only serious and unexpected ADRs found to have a reasonable suspected causal relationship to the drug should be reported by the sponsor to HC.

Per the CanadaFDR and the G-CanadaCTApps, during a clinical trial, the sponsor is required to inform HC of any serious, unexpected ADR that has occurred inside or outside Canada. An ADR report must be filed in the following specified timelines:

  • When the ADR is neither fatal nor life-threatening, within 15 days after becoming aware of the information
  • When it is fatal or life-threatening, immediately when possible and, in any event, within seven (7) days after becoming aware of the information
  • Within eight (8) days after having informed HC of the ADR, submit a report that includes an assessment of the importance and implication of any findings

Other Safety Reports

The G-DSUR delineates that the development safety update report (DSUR) and the DSUR Checklist (CAN-38) should be provided, upon request, directly to the Office of Submissions and Intellectual Property (OSIP). HC recommends that DSURs in electronic Common Technical Document (eCTD) format be sent via the Common Electronic Submission Gateway (CESG) and DSURs in "non-eCTD electronic-only" format be sent to OSIP via CD/DVD. Sponsors may provide DSURs when important new safety information on a drug needs to be conveyed as long as a strong rationale for the filing of the DSUR is included in the cover letter. For additional details, see the G-DSUR.

The G-DSUR-CanUK describes the region-specific requirements for DSURs submitted to the regulatory authorities of Canada and the United Kingdom. This guidance applies to both marketed and non-marketed drugs that are used in clinical trials and applies to DSURs prepared by the manufacturer and/or marketing authorization holder of the investigational drug.

Form Completion & Delivery Requirements

As per the G-CanadaCTApps, the HCNotice-E2A, and CAN-22, all serious and unexpected ADRs should be reported individually to HC. According to HC-ICH-E2A (which Canada adopted pursuant to the HCNotice-E2A), at a minimum, the report should include an identifiable patient, the name of a suspect medicinal product, an identifiable reporting source, and an event or outcome that can be identified as serious and unexpected and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. The G-CanadaCTApps requires the sponsor to complete the expedited reporting form (CAN-5) and the CIOMS Form I (CAN-7) and fax them to the appropriate HC Directorate: BRDD Fax: 613-957-0364; PDD Fax: 613-941-2121.

1.1, 1.2, 1.50, 1.60, and 4.11
Part C (Division 5 (C.05.001 and C.05.014))
2.1 and 2.8
Notice, 1.2, and 2.4
5.14
Chapter 11 (Article 11.8)
Attachment 1
Last content review/update: February 24, 2022

Overview

According to GBR-1 and GBR-64, the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

  • Adverse Event (or Adverse Experience) (AE) – Any untoward medical occurrence in a participant, including occurrences which are not necessarily caused by or related to that product
  • Adverse Drug Reaction (ADR) – Any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant
  • Serious Adverse Event (SAE), Serious Adverse Drug Reaction (SADR), or Unexpected Serious ADR – Any AE, ADR, or unexpected ADR that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect
  • Unexpected Adverse Drug Reaction (ADR) – An adverse reaction where the nature or severity is inconsistent with the applicable product information
  • Suspected Unexpected Serious Adverse Reaction (SUSAR) – A suspected serious adverse reaction, which is also “unexpected,” meaning that its nature and severity are not consistent with the information about the medicinal product in question.

Per the G-CTAuth, the Medicines and Healthcare Products Regulatory Agency (MHRA) advises that the guidance on reference safety information (RSI) contained in GBR-30 (developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies (HMA)) remains applicable. For clinical trials that are being conducted in the UK, an RSI cannot be used for expectedness until the RSI has been approved by MHRA. Additional SUSARs that occur before the new RSI is approved should be reported in the usual expedited manner. If sponsors wish to harmonize the implementation date of an RSI in a trial that includes European Union (EU) and UK sites, then they can use the date when approval is granted in all member states and the UK. In the interest of efficiency and harmonization for multinational trials, the MHRA recommends that amendments including changes to the RSI are submitted to the UK and EU at the same time. The RSI in place at the time the SUSAR occurred should be used to assess expectedness for follow-up reports.

Reporting Requirements for AEs/ADRs

Investigator Responsibilities

As specified in the MHCTR, GBR-1, and GBR-30, the investigator is responsible for reporting all SAEs/SADRs immediately to the sponsor. The report may be made orally or in writing, and followed by a detailed report no later than 24 hours after the event. When the reported event results in a participant’s death, the investigator must provide the sponsor with any requested information. According to the MHCTR, in cases where reporting is not immediately required according to the protocol or the Investigator’s Brochure (IB), the investigator should report an SAE/SADR within the appropriate timeframe based on the trial requirements, the seriousness of the SAE/SADR, and protocol or IB guidelines. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

Sponsor Responsibilities

According to the MHCTR, the G-CTAuth, the MHCTR-EUExit, GBR-115, and GBR-99, the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days to the MHRA, to the institution in which the trial is being conducted, and to the ethics committee (EC). Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life-threatening SUSARs no later than 15 calendar days following first awareness of the event. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness. Per the G-CTAuth, sponsors must report all UK-relevant SUSARs to the MHRA. The agency’s definition of ‘UK-relevant’ includes:

  • SUSARs originating in the UK for a trial
  • SUSARs originating outside the UK for a trial
  • If the sponsor is serving as a sponsor of another ongoing trial outside the UK involving the same medicinal product
  • SUSARs involving the same medicinal product if the sponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the UK sponsor

Per the G-CTAuth and the G-SftyRpts, sponsors must submit Development Safety Update Reports (DSURs) to the MHRA. G-CTAuth specifies that the DSUR should take into account all new available safety information received during the reporting period. The DSUR should include:

  • A cover letter listing all relevant clinical trial numbers of trials covered by the DSUR and an email address for correspondence (Note: per GBR-18, every clinical trial with a European site must include a unique European Clinical Trials Database (EudraCT) number (GBR-87))
  • An analysis of the participant’s safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
  • A listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s)
  • An aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)

At the end of the DSUR reporting period, the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the Investigator’s Brochure as a substantial amendment. This amendment must be supported by the DSUR and approved before the RSI is changed.

A shortened DSUR is available for approved trials under MHRA’s notification scheme that are not part of a multi-study development program. Phase 4 national (UK only) trials of licensed products, which commanded a low fee from the MHRA, and where all participants have completed treatment and are only in the follow-up stage will also be suitable for submission of a short format DSUR. As an alternative to producing a full DSUR for these trials, the Health Research Authority Annual Progress Report (GBR-27) may be used.

MHRA and Health Canada jointly released DSUR-UK_Canada to strengthen patient safety in clinical trials by improving the quality of DSURs. To increase the transparency of the data included in DSURs, MHRA and Health Canada are requiring that the region-specific section of the DSUR explain how safety data were reviewed during the reporting period. Specifically, the region-specific section of the DSUR should include a summary description of the processes used by the sponsor to review the worldwide safety data of the investigational product (IP) (e.g., regular analyses of accumulating data, in-house safety review meetings, proposal of specific pharmacovigilance activities, or substantial modifications of protocol). In addition, the region-specific section must describe how each safety signal (i.e., an event with an unknown causal relationship to the IP) identified during the reporting period was evaluated, as well as how a decision was made regarding the signal itself.

Per GBR-99, a sponsor or investigator may take appropriate urgent safety measures (USMs) to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body. The main EC, and the MHRA for clinical trials for investigational medicinal products (CTIMPs), must be notified immediately (no later than three (3) days) in the form of a substantial amendment that such measures have been taken and the reasons why. The G-CTAuth states that the sponsor should call the MHRA’s Clinical Trials Unit at 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken, but no later than three (3) days. If key details are not available during the initial call, then the sponsor should inform MHRA no later than three (3) days from the date the measures are taken by email to clintrialhelpline@mhra.gov.uk. Written notification in the form of a substantial amendment is also required. The substantial amendment covering the changes made as part of the USM is anticipated within approximately two (2) weeks of notification to the MHRA. Any potential reason for delay of substantial amendment submission should be discussed and agreed upon with the MHRA at the time of initial notification or through a follow-up call. Submission of the substantial amendment must not be delayed by additional changes outside of those taken and required as an urgent safety measure. Unrelated and unacceptable changes may result in rejection. For more details on how submissions should be made using MHRA Submissions, see G-CTAuth.

See the G-CTAuth, the MHCTR, GBR-1, GBR-30, and GBR-99 for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

Per the G-CTAuth and the G-SftyRpts, SUSARs during clinical trials should be reported to the MHRA in one (1) of the following ways:

  • MHRA’s eSUSAR website (GBR-50) - Before using the eSUSAR website, users should complete the eSUSAR registration form (download from GBR-50) and email it to esusar@mhra.gov.uk with the subject line ‘eSUSAR registration’.
  • MHRA Gateway (which replaces the EudraVigilance Gateway) - To gain access to the MHRA Gateway, which is used to submit bulk reports, users must first register via MHRA Submissions (GBR-13). The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11.

If applicable, the user will need to dual report UK-relevant SUSARs to the Clinical Trial Module in the European Medicines Agency’s (EMA) EudraVigilance System, as well as to other national competent authorities, using the European submission routes.

G-SftyRpts provides details on how sponsors should submit DSURs using MHRA Submissions (GBR-13). Acknowledgements of receipt for DSUR submissions are generated by MHRA Submissions where a confirmation of submission is emailed to the reporter.

In addition, per GBR-99, copies of all UK-related safety information supplied to MHRA must also be emailed to the main EC. The EC manager will acknowledge receipt of all safety reports within 30 days by signing and returning a copy of the covering form. Reports sent without the covering form will not be acknowledged. See GBR-9 for information on the EC’s monitoring responsibilities for a clinical trial of an IP.

See the G-CTAuth, G-SftyRpts, GBR-50, and GBR-99 for more details on submittal and delivery requirements.

Data Monitoring Committee (DMC)

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Reference Safety Information - updated guidance, Suspected Unexpected Serious Adverse Reactions (SUSARs), Development Safety Update Reports (DSURs), and Urgent Safety Measures
Reporting SUSARs using the new reporting routes, Registering for MHRA Gateway, Reporting SUSARs using the eSUSAR website, Transition between reporting to EU and UK systems, and Submitting DSURs to the MHRA
Part 5
14
4 and 5
1, 4.11, 5.16, 5.17, and 5.5
CI Checklist Before Seeking Approval, Safety Reporting, and Urgent Safety Measures
SUSAR
10

Clinical Trial Lifecycle > Progress Reporting

Last content review/update: August 11, 2022

Interim and Annual Progress Reports

Pursuant to the CanadaFDR, the G-CanadaCTApps, CAN-22, and the CA-ICH-GCPs, investigators and sponsors share responsibility for submitting interim and annual reports on the status of a clinical trial. The investigator is required to provide annual progress reports to the institutional ethics committee (EC) and submit interim progress reports to the EC and Health Canada (HC) if there are any significant changes affecting the trial or risk to participants. The sponsor is required to submit annual reports (in the form of an updated Investigator’s Brochure (IB)) to HC. Note that per HCNotice-CA-ICH-GCPs, HC-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

As per the CA-ICH-GCPs, the investigator should promptly provide written reports to the sponsor and the institutional EC on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

According to the G-TCPS2, investigators must report new information that may affect the welfare or consent of participants to the institutional EC, HC, and other appropriate regulatory or advisory entities. When new information is relevant to participants’ welfare, researchers must promptly inform all participants to whom the information applies (including former participants). Researchers should work with their ECs to determine which participants must be informed, and how the information should be conveyed. New information may comprise a range of issues, including, but not limited to:

  • Changes to the research design
  • Evidence of any new risks
  • Unanticipated issues that have possible health or safety consequences for participants
  • New information that decisively proves the benefits of one (1) intervention over another
  • New research findings, including relevant non-trial findings
  • Unanticipated problems
  • Closure of trials at other sites for reasons that may be relevant to the welfare or consent of participants in the ongoing trial

Pursuant to the CA-ICH-GCPs, the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested.

Final Report

Upon completion of the trial, as delineated in CA-ICH-GCPs, the investigator is required to submit a final report to the institutional EC summarizing the trial’s outcome. The CanadaFDR does not require submission of a final study report to HC.

4.10 and 4.13
Part C (Division 5 (C.05.012 and C.05.013))
2.8
5.12 and 5.13
Chapter 11 (Article 11.8)
Last content review/update: February 24, 2022

Overview

As indicated in the G-CTAuth, GBR-65, and GBR-9, the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113).

Interim and Annual Progress Reports

In accordance with GBR-65 and GBR-9, the chief investigator (CI) is responsible for submitting progress reports annually, or more frequently if requested by the ethics committee (EC), on the status of a clinical trial. Per GBR-65, a progress report should be submitted to the EC 12 months after the date on which the favorable opinion was given. Progress reports are only required for studies that are more than two (2) years in duration and for Research Tissue Bank and Research Databases. There is no requirement to submit a progress report for proportionate review studies and where the study is two (2) years or less in duration. The form (GBR-27) should be completed in typescript and signed by the CI. An electronic copy should be emailed to the EC within 30 days of the end of the reporting period.

Health Research Authority (HRA)-approved research projects that have also been reviewed by an EC should submit regular progress reports to the HRA using the guidance outlined for ECs above. See GBR-18 for additional information on clinical trial progress reporting.

Final Report

As per the MHCTR and the G-CTAuth, the sponsor must notify the Medicines and Healthcare Products Regulatory Agency (MHRA) and the EC in writing that a clinical trial has ended within 90 days of the conclusion of the trial. The G-CTAuth further specifies that a declaration of the end of a clinical trial should be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end of trial form (GBR-24) and a cover letter. Note that only the global end-of-trial notification is required to be submitted. However, a facility may inform MHRA of the local (UK) end of trial via the end-of-trial notification form, but these local notifications will not be officially acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, MHRA would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received. An exemption to this requirement must be requested via a substantial amendment for approval. The amendment must clearly state to what documents the proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK. Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end-of-trial declaration form. It is not possible to submit amendments to the trial or the Development Safety Update Report (DSUR) once the global end-of-trial declaration form has been received by the MHRA. If the end-of-trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required. Sponsors must submit end-of-trial declarations using MHRA Submissions (GBR-13). G-MHRASubmiss and GBR-11 outline the steps for gaining access to MHRA Submissions.

Per the G-CTAuth, the timeframe for publishing the summary of results is within one (1) year of the end of trial. Sponsors should publish summary results within this timeframe in the public register(s) where they registered the clinical trial. While it is not required to submit this clinical trial summary report to the MHRA, sponsors must send a short confirmation email to CT.Submission@mhra.gov.uk once the results-related information has been uploaded to the public register and provide the relevant link. The G-CTAuth specifies that the subject line of the email notification must state ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ once the result-related information has been uploaded to the public register. If the clinical trial is not on a public register or the results will not be published in the register (for example an adult phase I study), summary results should be submitted to MHRA via MHRA Submissions (GBR-13). An acknowledgement letter will not be sent for this submission. Sponsors of trials conducted in the UK that are already registered in the European Union (EU) Register are able to submit results to EudraCT (GBR-87). The MHRA will not be able to update the status of the study in the EU system.

As per GBR-9 the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. GBR-20 clarifies that the form in GBR-20 should be used for this submittal, which includes submitting a lay summary of results. This is a UK-wide final report for all project-based research studies that have been reviewed by an EC within the UK Health Departments' Research Ethics Service (GBR-62). The information contained in this final report helps the Research Ethics Service to monitor whether the research was conducted in accordance with the EC’s favorable opinion and applicable transparency requirements. Per the GBR-120, sponsors should include a plain language summary of their findings in the final report, which will be published on HRA’s website alongside the study research summaries. See GBR-120 for guidance on writing a good plain language summary for a general audience.

End of Trial
Part 3 (Section 27)
4.10 and 4.13
Progress Reporting
Terminology (Glossary), and Sections 1 and 14

Sponsorship > Definition of Sponsor

Last content review/update: August 11, 2022

As per the CanadaFDR and the G-CanadaCTApps, a sponsor is defined as an individual, corporate body, institution, or organization that conducts a clinical trial. The CA-ICH-GCPs expands on this definition to include individuals, companies, institutions, or organizations that take responsibility for the initiation, management and/or financing of a clinical trial.

In accordance with the CA-ICH-GCPs, Canada also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

According to the CanadaFDR and G-CanadaCTApps, a sponsor may be domestic or foreign. A foreign sponsor is required to have a senior medical or scientific officer who is residing in Canada who will represent the sponsor, and sign and date the application and the clinical trial attestation form.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

1.53, 5.1, and 5.2
Part C (Division 5 (C.05.001, C.05.005, C.05.015)
2.1
5.1 and 5.5
Last content review/update: February 24, 2022

Overview

As per the MHCTR, the MHCTR2006, the G-CTApp, GBR-103, GBR-9, GBR-2, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards, and arrange for the trial to be properly conducted and reported. In addition, per GBR-101, the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with GBR-113, the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Per the G-CTApp and the GBR-103, a clinical trial sponsor needs to be established in the UK or a country on an approved country list which initially includes the European Union (EU)/European Economic Area (EEA) countries per G-CTApprovedCountries. If this is not the case, then the sponsor must have a legal representative who is so established. The GBR-103 specifies that details of the legal representative should be entered in the ‘legal representative’ section of the Integrated Research Application System (IRAS) (GBR-78). The legal representative:

  • May be an individual person or a representative of a corporate entity
  • Does not have to be a legally qualified person
  • Should be willing to act as the agent of the sponsor in the event of any legal proceedings instituted (e.g., for service of legal documents)
  • Should be established at an address in the UK or a country on the approved country list
  • Does not assume any of the legal liabilities of the sponsor(s) for the trial by virtue of the role of legal representative and does not therefore require insurance or indemnity to meet such liabilities; but may, in some cases, enter into specific contractual arrangements to undertake some or all of the statutory duties of the sponsor in relation to the trial, in which case the legal representative would also be regarded as a co-sponsor and would then require insurance or indemnity cover

The MHCTR also permits two (2) or more parties to take responsibility for the sponsor’s functions. When this applies, the MHCTR requires one (1) of the parties to submit the clinical trial application for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA), and to specify who is responsible for carrying out the following functions:

  • Communications relating to substantial amendments, modified amendments, and the conclusion of the trial
  • Communications relating to urgent safety measures
  • Pharmacovigilance reporting

Per the G-SubtlAmndmt, the UK requires the sponsor or legal representative of a clinical trial to be in the UK or a country on an approved country list that will initially include the EU and EEA countries. A change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committee.

Trial Sponsor and legal Representative
2
Changes to the trial sponsor/legal representative
Part 1 (3)
Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
Responsibilities
5.1 and 5.2
Basic Principles
Terminology (Statutory Definitions Relating to CTIMPs)

Sponsorship > Site/Investigator Selection

Last content review/update: August 11, 2022

Overview

As set forth in the CA-ICH-GCPs, the sponsor should select the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by training and experience. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s). Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

In accordance with the G-CanadaCTApps, prior to initiating a clinical trial, the sponsor must ensure that a Qualified Investigator Undertaking (QIU) form (CAN-37) (or similar documentation that meets the CanadaFDR requirements) has been completed and kept on file by the sponsor. Per the CanadaFDR, the form certifies that the qualified investigator will conduct the clinical trial in accordance with good clinical practices, and will immediately inform trial participants and the institutional ethics committee (EC) (known as Research Ethics Boards in Canada) of trial discontinuance, and the reason for this discontinuance. (See the Submission Content section for additional information on clinical trial application requirements).

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Per CAN-27, the Canadian Clinical Trials Asset Map (CCTAM) (CAN-26) is an interactive pan-Canadian research inventory of investigators, clinical research sites, and other resources across the country. Sponsors can use CCTAM to identify potential sites and investigators, which may expedite study feasibility and start-up timelines. To view the CCTAM, the user must register and create an account.

Foreign Sponsor Responsibilities

According to the CanadaFDR and the G-CanadaCTApps, a sponsor may be domestic or foreign. A foreign sponsor is required to have a senior medical or scientific officer residing in Canada represent the sponsor, and sign and date the application and the clinical trial attestation form.

Data Safety and Monitoring Board

Although not specified as a sponsor requirement, the CA-ICH-GCPs states that a Data and Safety Monitoring Board (DSMB) (known as an Independent Data-Monitoring Committee in Canada) may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

The G-TCPS2 provides the following considerations to help researchers and ECs determine whether a DSMB is needed:

  • The magnitude of foreseeable research-attributable harms to participants
  • Whether the circumstances of the participants make them vulnerable in the context of research
  • The feasibility of interim data analysis
  • The complexity of the study
  • Conflicts of interest

Multicenter Studies

Per the CA-ICH-GCPs, if a multicenter trial will be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. In addition, the sponsor must ensure that:

  • All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and, if required, by HC
  • The EC has given approval to the protocol
  • The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
  • The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
  • All investigators are given instructions on following the protocol, on complying with a uniform set of standards to assess clinical and laboratory findings, and on completing the CRFs
  • Communication between investigators is facilitated

The CanadaFDR, the G-CanadaCTApps, and the G-CanadaNon-eCTD, require the sponsor to complete and retain the Research Ethics Board (REB) Attestation (CAN-8) and Qualified Investigator Undertaking (QIU) (CAN-37) forms at each trial site, while submitting in electronic format the Clinical Trial Site Information form (CAN-6) to the appropriate HC Directorate for each trial site.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, provides that in multi-site clinical trials, a lead principal investigator (PI) is a designated PI who is responsible for the ethical conduct of the study for all sites. The lead PI is responsible for communicating any changes to the study, new information, and/or unanticipated events to the EC, to the sponsor, and to local site PIs.

Per HCNotice-ICH-E17, HC announced the implementation of CAN-40, which describes general principles for the planning and design of multi-regional clinical trials with the aim of increasing the acceptability of these trials in global regulatory submissions. HC recognizes that the scope and subject matter of current HC guidance may not be entirely consistent with ICH guidance. In such circumstances, HC-implemented ICH guidance takes precedence.

1.25, 5.5, and 5.6
Part C (Division 5 (C.05.005))
2.1 and 2.7.2
1-3 and 3-3
5.5
Chapter 11 (Article 11.7)
Last content review/update: February 24, 2022

Overview

As set forth in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 indicates that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study.

As delineated in the MHCTR, the MHCTR2006, and GBR-113, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per GBR-113, if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. Per GBR-18, for clinical trials of investigational products conducted at National Health Service (NHS) sites, the addition of a new site and/or addition or change of a principal investigator (PI) is no longer considered a substantial amendment. No changes have been made to the classification of amendments relating to new sites/change of PI at non-NHS sites. If a site is added in a nation not previously involved in a study, this should be indicated in the amendment section of the Integrated Research Application System (IRAS) (GBR-78) and made clear in a cover letter when submitting the amendment to the lead nation.

GBR-113 recommends establishing a Data Monitoring Committee (DMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Per GBR-63, the United Kingdom (UK) launched the UK Local Information Pack. Researchers working with NHS / Health and Social Care in Northern Ireland (HSC) organizations will use one (1) consistent package to support study setup and delivery across the UK. The Statement of Activities (used in England and Wales) and the Site Specific Information form (used in Northern Ireland and Scotland) are being replaced with a UK-wide Organizational Information document. The Organizational Information document will be a component of the GBR-78 form submission and will be required as part of the UK Local Information Pack for both commercial and non-commercial research. GBR-106 provides guidance, background information, and templates of the commercial and non-commercial versions of the Organizational Information document.

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list (which initially includes European Union (EU)/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Per the G-CTApprovedCountries, the UK published a list of countries where a sponsor of a clinical trial, or their legal representative, may be established; currently listed countries are those in the EU and EEA. The G-SubtlAmndmt delineates that a change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committee (EC), pursuant to the guidelines in the G-CTAuth. Where the sponsor is from the rest of the world, and the legal representative is established in the UK, and there are sites in the EU/EEA, the sponsor will need to assign an EU/EEA legal representative for these sites via a substantial amendment to the relevant EU/EEA competent authorities. No amendment submission to the MHRA is required where the sponsor or legal representative for an ongoing trial is established in the EU/EEA as the UK will continue to accept this approval. Further, no amendment will need to be submitted in the UK if the sponsor retains the UK legal representative for the UK study. Similarly, no amendment will need to be submitted in the UK if a sponsor remains in the UK and a legal representative is added to cover EU/EEA sites.

Additional foreign sponsor requirements are listed in Section 5.2 of GBR-113.

Data Safety and Monitoring Board

Per GBR-18, the chief investigator should ensure that arrangements are made for a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK). The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

As delineated in GBR-113, in the event of a multicenter clinical trial, the sponsor must ensure that:

  • All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor
  • The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
  • Investigator responsibilities are documented prior to the start of the trial
  • All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
  • Communication between investigators is facilitated
2
Amending your trial protocol or other documentation
Changes to the trial sponsor/legal representative
Part 1 (3) and Part 3 (15)
Insertion of Regulation 3A of the Principal Regulations, Insertion of Regulation 29A of the Principal Regulations, and Part 2 (Principles based on Articles 2 to 5 of the GCP Directive)
Preparing and Submitting Application (Site-specific information)
5.23, 5.5, 5.6, 6, and 7
CI Checklist Before Seeking Approval and Addition of New Sites & Investigators

Sponsorship > Insurance & Compensation

Last content review/update: August 11, 2022

Insurance

The CanadaFDR does not require the sponsor to provide insurance coverage to investigators, institutions, or trial participants. However, the CA-ICH-GCPs guides sponsors on providing insurance. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

Compensation

Injury or Death

The Canadian regulations do not require compensation for trial participants in the event of trial-related injuries or death. However, the CA-ICH-GCPs indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries. Note that per HCNotice-CA-ICH-GCPs, HC-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

Trial Participation

The Canadian regulations do not require compensation for trial participation. However, as per the G-TCPS2 and the CA-ICH-GCPs, the informed consent form (ICF) should contain a statement with a description of the anticipated prorated payment to the participant(s) that is reasonably expected for participation in the trial. Any compensation or incentive to participants must not be so excessive that it may unfairly influence participants, or cause them to overlook important facts and risks. CAN-35 furthers states that the ICF should describe any compensation, incentives, or reimbursements to be paid or given to participants and how participant withdrawal will affect the offered compensation (e.g., prorated remuneration). If no compensation will be provided, this should be stated.

4.8 and 5.8
Chapter 3 (Article 3.2)
Policies, Guidelines, and Resources, Consent Process (Consent Form Template)
Last content review/update: February 24, 2022

Insurance

As set forth in the MHCTR and the MHCTR2006, it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial-related injuries. The MHCTR does not ascribe responsibility to the sponsor or his/her designated representative to obtain insurance and indemnity. However, GBR-2, GBR-103, GBR-101, and GBR-18, state that the sponsor or his/her designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

In addition, according to GBR-2, the sponsor or his/her designated representative must ensure that the research covered by the National Health Service (NHS)'s indemnity policy is in place for each publicly funded participating study site. See GBR-33 for detailed information on the NHS indemnity responsibilities for clinical negligence involving investigators and participants. GBR-33, specifically addresses the sponsor’s or his/her designated representative’s requirement to insure or indemnify the investigator participating in industry-sponsored Phase I clinical trials.

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) also guides sponsors on providing insurance.

Compensation

Injury or Death

As specified in the MHCTR, the sponsor or his/her designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase I trial-related injuries or death. According to GBR-33, the sponsor or his/her designated representative may be required to follow the principles set forth in the Association of the British Pharmaceutical Industry (ABPI)’s guidelines to comply with the United Kingdom (UK)’s participant compensation and treatment requirements due to Phase I trial-related injuries. The guidelines state that the sponsor should furnish written assurance to the investigator that the sponsor will agree to pay compensation to participants and/or his/her legal heirs in the event of trial-related injuries or death whenever a causal relationship with participation is demonstrated. The investigator, in turn, communicates this information to the relevant ethics committees (ECs).

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) also provides guidance for sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

Part 3 (15), Part 4 (8), and Schedule 1 (Part 1 (1) and (16))
Part 2 (Conditions Based on Article 3 of the Directive)
Responsibilities
5.8
CI Checklist Before Seeking Approval (Trial Planning Phase) and Final Trial Management Documentation
Introduction and Basic Principles
3, 4 and 6

Sponsorship > Risk & Quality Management

Last content review/update: August 11, 2022

Quality Assurance/Quality Control

Per the CA-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. Per CAN-48, Canada implements the International Council for Harmonisation (ICH) of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance E8(R1): General Considerations for Clinical Studies (CAN-49), which provides guidance on conduct during the clinical trial. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

The quality management system should use a risk-based approach that includes:

  • During protocol development, identifying processes and data that are critical to ensure participant protection and the reliability of trial results
  • Identifying risks to critical trial processes and data
  • Evaluating the identified risks, against existing risk controls
  • Deciding which risks to reduce and/or which risks to accept
  • Documenting quality management activities and communicate to those involved in or affected by these activities
  • Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
  • In the clinical study report, describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken

As stated in the CanadaFDR and the CA-ICH-GCPs, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the CA-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that both parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per the HCNotice-ICH-E9, HC adopted and implements the ICH guidance on statistical principles for clinical trials (HC-ICH-E9), as well as the ICH addendum on estimands and sensitivity analysis (CAN-39), which presents a framework for defining an appropriate estimand for a clinical trial and conducting sensitivity analyses.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Audit Requirements

As part of its QA system, the CA-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the CA-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditors’ qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Premature Study Termination/Suspension

The CanadaFDR states that if a trial is prematurely terminated or suspended, the sponsor should inform HC no later than 15 days after the termination or suspension. In addition, the sponsor should provide HC with the reason(s) for the termination or suspension and its impact on the proposed or ongoing clinical trials related to the drug in Canada by the sponsor. The sponsor should also promptly notify the qualified investigators of the termination or suspension and advise them in writing of any potential risks to the participants’ health. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

According to the CA-ICH-GCPs, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the ethics committee (EC) should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

1.65, 5.0, 5.1, 5.2, 5.18, 5.19, 5.21, 5.23, and 6.10
Purpose and Scope, and Glossary
Part C (Division 5 (C.05.007-008, C.05.010, and C.05.015))
5.10 and 5.15
Last content review/update: February 24, 2022

Quality Assurance/Quality Control

As stated in the MHCTR, the MHCTR2006, and GBR-92, the sponsor is responsible for maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). The sponsor is required to obtain agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

  • Conduct the trial in compliance with GBR-113 and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
  • Comply with data recording and reporting procedures
  • Permit monitoring, auditing, and inspection
  • Retain essential documents until the sponsor informs them that they are no longer needed

MHCTR2006 requires the sponsor to notify the Medicines and Healthcare Products Regulatory Agency (MHRA) of serious breaches of good clinical practice (GCP) or the trial protocol. A serious breach is defined as one that is likely to effect to a significant degree: the safety or physical or mental integrity of the trial participants; or the scientific value of the trial. Per G-MHRA-SeriousBreaches, the sponsor, or delegated party, should notify the MHRA GCP Inspectorate within seven (7) days of becoming aware of a serious breach. Further, the sponsor should investigate and take action simultaneously after the MHRA notification. Notifications should primarily be sent to the following email address: GCP.SeriousBreaches@mhra.gov.uk.

Audit and Inspection Requirements

Per GBR-18, the sponsor must develop an audit plan to assess and assure the reliability and integrity of the clinical trial systems against all relevant written standards. The following activities and checks could include the following:

  • Interview staff to assess whether they are appropriately trained, understand their role/s, and are working to all relevant standards, the protocol and procedures SOPs.
  • Tour the facility to assess if there are adequate resources and if the equipment is fit for its intended use.
  • Review documents to evaluate whether data reported is verifiable from source data and that written records confirm that the trial was conducted appropriately.

Auditors must be independent of the trial team and appropriately trained for their role. Their findings and observations must be documented in a formal audit report. Any deficiencies identified during an audit must be followed up with appropriate corrective and preventive actions wherever possible.

Per GBR-18, MHRA may conduct inspections to ensure the clinical trial is being conducted in compliance with good clinical practice as prescribed in GBR-92 and GBR-113. MHRA takes a risk-based approach to inspections depending on the type of trials and risk rating. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization. A response to this report (describing any corrective and preventive actions) must be produced.

Finally, the sponsor’s audits and inspections should be conducted in compliance with GBR-113, which calls for a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan). The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials.

Premature Study Termination/Suspension

The G-CTAuth states that the MHRA has the authority to suspend or terminate a trial. In addition, the sponsor can contact the MHRA to put a trial on temporary halt or terminate a trial. If a sponsor suspends a trial temporarily, the MHRA must be notified. The notification should be made as a substantial amendment using the notification of amendment form (GBR-25), clearly explaining what has been stopped and the reasons for the suspension. See G-CTAuth for details on how to submit substantial amendments relating to temporary suspension using MHRA Submissions (GBR-13). The G-MHRASubmiss and GBR-11 provide the steps for gaining access to MHRA Submissions (GBR-13). To restart a trial that has been temporarily suspended, the sponsor must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Per the G-CTAuth and GBR-18, to terminate a trial, the sponsor must complete the end of trial declaration form (GBR-24) and include a brief explanation of the reasons for ending the trial, particularly when the trial has been terminated early. See G-CTAuth for details on how to submit this form using MHRA Submissions (GBR-13). GBR-18 specifies that the sponsor must make the end of trial notification to regulatory authorities (MHRA in the UK) and ECs of all countries with sites within 90 days.

According to GBR-113, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the sponsor should also inform the EC promptly and provide the reason(s) for the termination or suspension.

Suspend or Terminate a Trial and End of Trial
5.0, 5.1, 5.2, 5.18, 5.19, 5.21, and 6.10
Ongoing Management & Monitoring, MHRA Inspection, Temporary Halt, Early Termination, and End of Trial Declaration
Part 3 (15), Part 4 (28), Part 6 (36 and 38), and Schedule 7 (Parts 2 and 3)
Amendment of Regulation 31 of the Principal Regulations and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive)

Sponsorship > Data & Records Management

Last content review/update: August 11, 2022

Electronic Data Processing System

Per the CA-ICH-GCPs, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain SOPs that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the CA-ICH-GCPs for additional information.

The G-FDR-0100 provides that if electronic records are generated during a clinical trial, then the electronic system must be validated to confirm that the system’s specifications meet the goals and requirements for the clinical trial. This evidence of validation should be kept for the required record retention period and available for inspection by HC inspectors. See the G-FDR-0100 for additional details.

Records Management

As set forth in the CanadaFDR and the CanadaFDR1024, the sponsor must record, handle, and store all trial-related information to allow complete and accurate reporting, interpretation, and verification. The CanadaFDR requires the sponsor to maintain all trial-related records for a period of 15 years. Pursuant to CanadaFDR1024, the sponsor must submit requested records to HC within 48 hours if safety concerns arise. Additionally, to facilitate inspection of a site, the sponsor must submit information to HC within seven (7) days of a request. Per CAN-8, an attestation must be completed by the ethics committee that reviewed and approved the clinical trial. The completed attestation must be retained by the clinical trial sponsor for a period of 15 years. The attestation should not be submitted to HC unless requested.

In addition, the CA-ICH-GCPs states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

5.5and 8
Part C (Division 5 (C.05.012))
Regulatory Impact Analysis Statement
5.12
Last content review/update: February 24, 2022

Electronic Data Processing System

To safeguard personal data within electronic health record (EHR) systems, G-EHRAccess provides guidance on updating these systems to ensure access by sponsors and their representatives (e.g., monitors and investigators) is limited to only the records of clinical trial participants and that this access is auditable. See G-EHRAccess for details on system security, remote access, document sharing, consent, and other considerations.

According to GBR-113, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain SOPs that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.

Records Management

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

In addition, GBR-113 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

1.65, 5.18, and 8
Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive)

Sponsorship > Personal Data Protection

Last content review/update: August 11, 2022

Responsible Parties

No information is currently available.

Data Protection

Per CAN-42, the Office of the Privacy Commissioner of Canada provides advice and information for individuals about protecting personal information, and enforces the two (2) federal privacy laws that set out the rules for how federal government institutions and certain businesses must handle personal information, including health data. The PIPEDA covers the personal information-handling practices of federal government departments and agencies in Canada, and the PrivAct regulates private businesses’ data protection practices. In addition, some provinces and territories have laws that deal specifically with protection of personal health information. See CAN-43 for a list of provincial and territorial privacy laws and webpages.

Consent for Processing Personal Data

Both PIPEDA and the PrivAct require consent for the use of personal data, including health data, except under prescribed conditions, such as for research or during emergencies. Also see CAN-43 for provincial and territorial privacy laws.

Part I (2, 6.1, and 7)
3, 7, and 8
Last content review/update: February 24, 2022

Responsible Parties

For purposes of data protection requirements, the UK-GDPR, the UK-DPAct, and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database. GBR-7 provides guidance on key data protection requirements to consider in the post-Brexit environment. Among other things, it describes how data can continue to flow to and from the UK, as well as controller responsibilities.

Data Protection

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the sponsor (known as the “controller” in data protection legislation) must comply with the principles of the data protection legislation:

  • Lawfulness, fairness, and transparency
  • Purpose limitation
  • Data minimization
  • Accuracy
  • Storage limitation
  • Integrity and confidentiality (security)
  • Accountability

The sponsor must show that each activity of processing data has a lawful basis under this legislation, in addition to the common law basis. For health and social care research, the lawful basis is determined by the type of organization that is the data controller for the processing:

  • For universities, National Health Service (NHS) organizations, Research Council institutes, or other public authority, the processing of personal data for research should be a “task in the public interest.”
  • For commercial companies and charitable research organizations, the processing of personal data for research should be undertaken within “legitimate interests.”

As described in the G-GDPR, with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data. See the table in G-GDPR, which sets out the specific transparency requirements for personal data. In addition, GBR-100 contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see GBR-100. For additional information about consent and individual rights, see the Documentation Requirements and Required Elements sections.

Per the UK-GDPR and the UK-DPAct, the data protection legislation introduces a duty requiring public authorities or bodies to appoint a data protection officer (DPO); a DPO may be required for non-public entities if they carry out certain types of processing activities. The DPO assists the sponsor with monitoring internal compliance, informs and advises on data protection obligations, provides advice regarding Data Protection Impact Assessments (DPIAs), and is a point of contact for participants and the supervisory authority. See G-GDPR for guidance related to DPIAs.

For more information on data protection requirements following the United Kingdom’s (UK) transition out of the European Union (EU), see GBR-7.

Consent for Processing Personal Data

Per the UK-GDPR, UK-DPAct, and G-GDPR, consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. As indicated in the G-GDPR and GBR-100, the HRA has developed a series of templates to help organizations comply with the data protection legislation. The requirements vary depending on the point of collection of personal data (directly or indirectly) and the timing of the study (i.e., before or after May 25, 2018).

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, participants have the right to be informed about the collection and use of their personal data. This is a key transparency requirement under the data protection legislation. The UK-GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the participant has certain data rights, which are limited by a range of exemptions. These exemptions must be balanced with what is fair to participants. As indicated in the G-GDPR, exemptions to data subject rights are not automatic, but must be considered on a study-by-study basis. It is important, therefore, to take into account the relevance of data rights to a particular study in the Participant Information Sheet (PIS) when offering or limiting the rights available to research participants. If data rights have been previously offered or limited to participants that are not appropriate under UK-GDPR, then the PIS may need to be revised as a non-substantial amendment.

What the Law Says, What You Need to do
Part 1, Part 2 (Chapter 2), and Schedules 2-4
Chapter I (Article 4), Chapter II (Articles 5 and 6), Chapter III (Articles 12-23), and Chapter IV (Articles 24-43)
Principles, Lawful Basis for Processing, Individual Rights, Accountability and Governance

Informed Consent > Documentation Requirements

Last content review/update: August 11, 2022

Obtaining Consent

In all Canadian clinical trials, a freely given informed consent is required from each participant in accordance with the requirements set forth in the CanadaFDR, the G-TCPS2, the CA-ICH-GCPs, and CAN-35. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

As per the CanadaFDR, the G-TCPS2, and the CA-ICH-GCPs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a Research Ethics Board (REB) in Canada) and provided to HC with the clinical trial application (CTA). (See the Required Elements section for details on what should be included in the form.)

The G-TCPS2 and the CA-ICH-GCPs state that the qualified investigator (QI) must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). As delineated in the G-TCPS2, CAN-35, and the CA-ICH-GCPs, the ICF content should be in plain language (i.e., non-technical and easy to understand) and provided in a format that facilitates understanding. For example, written documentation may be supplemented with audio and/or visual aids. The participant and his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate. CAN-35 notes that the person obtaining consent may also need to explain the consent form verbally to ensure that the participant fully understands the information. See CAN-35 for informed consent and assent templates and sample forms.

Re-Consent

According to the CA-ICH-GCPs, any change in the ICF that is relevant to the participant’s consent should be approved by the institutional EC prior to implementing any changes. The participant and/or his/her legal representative(s) or guardian(s) should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented.

Per the G-TCPS2, consent must be maintained throughout the research project. Researchers have an ongoing duty to provide participants with all information relevant to their ongoing consent to participate in the research. Further, within the limits of consent provided by the participant, researchers should disclose to the participant any material incidental findings discovered in the course of research. Incidental findings are considered to be material incidental findings if they are reasonably determined to have significant welfare implications for the participant or prospective participant. Where material incidental findings are foreseeable, researchers should inform participants during the initial consent process. In addition, researchers should develop a management plan for review by the EC. For more information on how to address material incidental findings, see G-ConsentMatIncFindings.

Language Requirements

CAN-35 further specifies that consent forms should be provided in the language that participants are most comfortable with. The G-TCPS2 and the CA-ICH-GCPs require the ICF to be presented in plain language that the participant is able to understand. Per CAN-35, ICFs should be translated where it is relevant to particular communities. If there is a language barrier, the G-TCPS2 indicates that the qualified investigator should select an intermediary who has the necessary language skills to ensure effective communication. Further, per CAN-35, the level of language used should be appropriate to the age and comprehension/reading level of the participant population, generally at approximately a grade 6-8 reading level.

Documenting Consent

As per the CA-ICH-GCPs and CAN-35, the participant and/or his/her legal representative(s) or guardian(s), as well as the qualified investigator, must sign and date the ICF. The CA-ICH-GCPs and the G-FDR-0100 state that the QI should retain the signed ICF. CAN-35 indicates that information letters and ICFs must be presented on institutional/department letterhead.

According to the CA-ICH-GCPs, where the participant is illiterate and/or his/her legal representative(s) and/or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:

  • The written ICF and any other written information to be provided to the participant is read and explained to the participant and his/her legal representative(s) and/or guardian(s)
  • The participant and his/her legal representative(s) and/or guardian(s), have orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Before participating in the study, the participant or his/her legal representative(s) and/or guardian(s) should receive a copy of the signed and dated ICF.

As per the G-TCPS2 and the CA-ICH-GCPs, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) and/or guardian(s) to waive or appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representative(s) from their liabilities for any negligence.

Per CAN-35, in some situations, written consent is not be feasible or desirable, for example due to logistical issues or because of the preferences of the participants. In addition, some individuals may perceive written consent as an attempt to legalize the consent process, thereby creating mistrust. It is also important to recognize that in some cultures written consent is not consistent with community traditions. In these cases, it may be more appropriate to use a handshake, a verbal agreement, or oral consent. Article 10.2 of the G-TCPS2 further indicates that researchers use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (a consent log, audio or video recordings, or other electronic means). Evidence of consent may also be documented via completed questionnaires (in person, by mail, or by email or other electronic means). ECs should consider the power relationship that might exist between researchers and participants, and whether a waiver of the requirement for signed written consent may affect the welfare of the participants. If researchers plan to obtain non-written consent, they must explain their strategy to the EC.

Waiver of Consent

As explained in the G-TCPS2, there are research situations that call for alterations of consent. The EC may approve research that involves an alteration to the consent requirements if the EC is satisfied, and documents, that all of the following apply:

  • The research involves no more than minimal risk to the participants
  • The alteration to consent requirements is unlikely to adversely affect the welfare of participants
  • It is impossible or impracticable to carry out the research and to address the research question properly, given the research design, if the prior consent of participants is required
  • In the case of a proposed alteration, the precise nature and extent of any proposed alteration is defined
  • There is a plan to provide a debriefing (if any) that may also offer participants the possibility of refusing consent and/or withdrawing data and/or human biological materials
4.8, 8.2, and 8.3
Part C (Division 5 (C.05.005, C.05.006, C.05.008, and C.05.010))
5.5, 5.6, 5.8, 5.10, 5.12
Chapters 3 and 10
Policies, Guidelines, and Resources; Consent Process (Key Considerations)
Last content review/update: February 24, 2022

Overview

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR, the MHCTR2006, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). As per the MHCTR, the MHCTR2006, and GBR-9, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures (GBR-9) issued by England’s Health Research Authority (HRA). The ICF must be provided to the EC with the clinical trial application. (See the Required Elements section for details on what should be included in the form.) See GBR-8 for a summary of changes to GBR-9, and also refer to GBR-18 and GBR-69 for more on informed consent in the UK. Also see GBR-117 for an interactive web-based communications toolkit to help researchers and participants keep in touch after participation in a research study.

The MHCTR and G-ConsentPIS, state that the investigator(s) must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant, and his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate. Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data.

As provided in G-ConsentPIS, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study. GBR-6 sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone or digital multimedia. It also enables their informed consent to be documented using electronic signatures. This approach can supplement the traditional paper-based approach or, where appropriate, replace it.

Per GBR-31, the HRA guides researchers and ECs in taking a proportionate approach to seeking consent. A proportionate approach adopts procedures commensurate with the balance of risk and benefits so that potential participants are not overwhelmed by unnecessarily lengthy, complex, and inaccessible information sheets. Participants should be provided with succinct, relevant, truthful information in a user-friendly manner that promotes their autonomy. Specifically, the methods and procedures used to seek informed consent and the level of information provided should be proportionate to:

  • The nature and the complexity of the research
  • The risks, burdens, and potential benefits (to the participants and/or society)
  • The ethical issues at stake

Re-Consent

According to GBR-113, the EC should approve any change in the ICF due to a protocol modification before such changes are implemented. The participant and/or his/her legal representative(s) or guardian(s) will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per GBR-18, during a clinical trial, researchers should periodically reaffirm the willingness of participants to continue. If significant new information becomes available, participants should be reconsented using revised (and re-approved) consent documents so that their continued consent is confirmed.

Language Requirements

As stated in the MHCTR, applications to the EC and the Medicines and Healthcare Products Regulatory Agency (MHRA) and any accompanying material, such as the ICF content, should be presented in English.

Documentation Copies

The MHCTR states that the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. Where the participant is illiterate, and/or his/her legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Principles of consent
Part 1 (3), Part 3 (12, 15, 17, and 18), Schedule 1 (Part 1 (3) and Part 2), and Schedule 3 (Parts 1 and 3)
Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; Amendment of Schedule 1 to the Principal Regulations; Amendment of Schedule 3 to the Principal Regulations; and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive and Conditions Based on Article 3 of the Directive)
2, 4.4, 4.8, 8.2, and 8.3
Informed Consent
1 and 2
Introduction (Purpose and Scope), Terminology (Glossary), and Section 1

Informed Consent > Required Elements

Last content review/update: August 11, 2022

Based on the G-TCPS2, the CA-ICH-GCPs, and CAN-35, the informed consent form (ICF) should include the following statements or descriptions in plain language, as applicable (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

  • The study involves research and an explanation of its purpose and duration
  • The trial treatment(s) and the probability for random assignment to each treatment
  • The procedures to be followed, including all invasive procedures
  • The participant’s responsibilities
  • Those aspects of the trial that are experimental
  • Any reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
  • Any reasonably expected benefits; if no benefit is expected, the participant should be made aware of this
  • The disclosure of specific alternative procedure(s) or therapies available to the participant, and their important potential benefits and risks
  • Compensation and/or treatment available to the participant in the event of a trial-related injury
  • The anticipated prorated payment, if any, to the participant for participating in the trial
  • Any expenses the participant needs to pay to participate in the trial
  • That participation is voluntary, and that the participant can refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the participant is otherwise entitled
  • Information concerning the possibility of commercialization of research findings, and the presence of any real, potential, or perceived conflicts of interest on the part of the researchers, their institutions, or the research sponsors
  • Confidentiality of records identifying the participant will be maintained, and permission given to monitors, the auditors, the ethics committee (EC), and Health Canada (HC) to access the participant’s medical records to verify the procedures and/or data, without violating the confidentiality of the participant, insofar as the applicable laws and regulations permit, and that, by signing a written ICF, the participant or the participant’s legal representative(s) or guardian(s) is authorizing such access
  • That records identifying the participant will not be made publicly available, insofar as the applicable laws and/or regulations permit; if the results of the trial are published, the participant’s identity will remain confidential
  • The participant and/or his/her legal representative(s) or guardian(s) will be notified in a timely manner if information becomes available that may affect the participant’s willingness to continue
  • The qualified investigator’s contact information for further information regarding the trial and the rights of participants, and whom to contact in the event of a trial-related injury
  • The identity and contact information of a qualified designated representative who can explain scientific or scholarly aspects of the research to participants
  • Information on stopping rules, foreseeable circumstances, and/or reasons under which the participant’s involvement in the trial may be terminated
  • The approximate number of participants in the trial

Per CAN-35, if blood is taken, indicate total volume (e.g., teaspoons and milliliter equivalent) and note the possibility of bruising or swelling while giving blood, or other possible discomforts at the site where blood is drawn. Further, state that there may be minimal chance of infection and that discomforts experienced will be brief and transient.

CAN-35 also indicates that participants should not be told if an EC has approved the study, since this may appear to offer a guarantee of safety. Further, no clause or language should be used to excuse or appear to excuse investigators or other persons or institutions involved from liability for their negligence or other faults. Sample consent forms are available from the Research Ethics Board Secretariat upon request: hc.reb-cer.sc@canada.ca.

See the Vulnerable Populations and Consent for Specimen sections for further information.

4.8
Chapter 3
Policies, Guidelines, and Resources
Last content review/update: February 24, 2022

Overview

As delineated in the MHCTR, the MHCTR2006, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), prior to beginning a clinical trial, the chief investigator (CI) is required to obtain a favorable opinion from a recognized ethics committee (EC) for the written informed consent form (ICF) and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s).

No Coercion

As per the G-ConsentPIS and GBR-113, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) and/or guardian(s) to waive or to appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Informed Consent Form Required Elements

Based on the MHCTR, the G-ConsentPIS, and GBR-113, the ICF should include the following statements or descriptions, as applicable. (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

  • The study purpose, procedures, and duration
  • Study title and the study IRAS ID are clearly displayed
  • Approximate number of participants involved in the trial
  • The participant’s responsibilities in participating in the trial
  • Trial treatment schedule and the probability for random assignment to each treatment
  • Experimental aspects of the study
  • Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
  • Any benefits or prorated payment to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
  • A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
  • Compensation and/or medical treatment available to the participant in the event of a trial-related injury
  • Any additional costs to the participant that may result from participation in the research
  • That participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
  • The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Medicines and Healthcare Products Regulatory Agency (MHRA), the ECs, the auditor(s), and the monitor(s)
  • That the participant and/or his/her legal representative(s) or guardian(s) will be notified if significant new findings developed during the study may affect the participant's willingness to continue
  • Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
  • Foreseeable circumstances under which the investigator(s) may remove the participant without his/her consent

ICF examples and templates are provided in the G-ConsentPIS.

For more information about informed consent required elements, see GBR-18, GBR-113, GBR-100, GBR-31, and GBR-69.

Principles of consent
Part 1 (3), Part 3 (12 and 15), and Schedule 3 (Parts 1 and 3)
Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; and Amendment of Schedule 3 to the Principal Regulations
4.4 and 4.8
Informed Consent
1 and 2

Informed Consent > Participant Rights

Last content review/update: August 11, 2022

Overview

In accordance with the CanadaFDR, the G-TCPS2, and the CA-ICH-GCPs, Canada’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-TCPS2 and the CA-ICH-GCPs state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

The informed consent template in CAN-35 provides that if a participant has any questions about their rights, they should contact:

Health Canada-PHAC Research Ethics Board Secretariat
70 Colombine Driveway, Room 941C, PL: 0909C
Brooke Claxton Building, Tunney's Pasture
Ottawa, ON K1A 0K9
Telephone: 613-941-5199
Fax: 613-941-9093
hc.reb-cer.sc@canada.ca

The Right to Participate, Abstain, or Withdraw

As stated in the G-TCPS2 and the CA-ICH-GCPs, the participant and/or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

Per CAN-35, the participant should be assured that their participation is completely voluntary, and that they are under no obligation to participate and are free to withdraw at any time without consequence. It should be made clear that their decision to withdraw will not influence their relationship with the researcher in any way. The researcher should explain what will happen to participant samples or data if they choose to withdraw. If applicable, clearly state the point in the study at which removal of samples or data becomes difficult or impossible.

The Right to Information

As per the G-TCPS2 and the CA-ICH-GCPs, a potential research participant and/or his/her legal representative(s) or guardian(s) has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to the G-TCPS2 and the CA-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

Per CAN-35, the ICF should explain what information will be collected about participants and for what purpose, including the type of information that will be collected (e.g., will it be coded or de-identified?) and how it will be stored. Further, the ICF should state who will have access to the collected information, and describe the efforts that will be made to prevent the risk of participant re-identification. Limits to confidentiality and additional requirements for projects led by HC or the Public Health Agency of Canada (PHAC) are provided in CAN-35.

The Right of Inquiry/Appeal

The G-TCPS2 and the CA-ICH-GCPs state that the research participant and/or his/her legal representative(s) or guardian(s) should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or his/her rights.

The Right to Safety and Welfare

The CA-ICH-GCPs, which upholds the Declaration of Helsinki, clearly state that a research participant’s right to safety and the protection of his/her health and welfare must take precedence over the interests of science and society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

1.27, 3.1, and 4.8
Part C (Division 5 (C.05.001 and C.05.005))
5.1 and 5.5
Chapter 1 (Article 1.1), Chapter 2, and Chapter 3 (Articles 3.1 and 3.2)
Consent Process (Consent Form Template)
Last content review/update: February 24, 2022

Overview

In accordance with the MHCTR, the MHCTR2006, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the United Kingdom’s (UK’s) ethical standards promote respect for all human beings and safeguard the rights of research participants. The MHCTR states that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR, the G-ConsentPIS, and GBR-113, the participant or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the MHCTR, the G-ConsentPIS, and GBR-113, a potential research participant and/or his/her legal representative(s) or guardian(s) has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per the MHCTR and GBR-113, the arrangements to protect participants’ privacy should be provided in the application to the ethics committee, and the ICF should inform potential participants of any potential risk to their confidentiality.

The Right of Inquiry/Appeal

The MHCTR and GBR-113 state that the research participant and/or his/her legal representative(s) or guardian(s) should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

The MHCTR, the MHCTR2006, and GBR-113, state that a research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

Principles and Content
Part 1 (3 and 15), Schedule 1 (Parts 1, 2, and 5)
Amendment of Regulation 3 of the Principal Regulations; Amendment of Schedule 1 to the Principal Regulations; and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive and Conditions Based on Article 3 of the Directive)
4.8

Informed Consent > Emergencies

Last content review/update: August 11, 2022

The G-TCPS2 and the CA-ICH-GCPs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. As per the CA-ICH-GCPs, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or his/her legal representative(s) or guardian(s), or, if an effective treatment is lacking but the investigational product could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the ethics committee (EC) (known as Research Ethics Board in Canada) must approve the protocol in advance. The participant and/or his/her legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

Per G-TCPS2, research involving medical emergencies must be conducted only if it addresses the emergency needs of the individuals involved, and then only in accordance with criteria established in advance of such research by the EC. The EC may allow research that involves medical emergencies to be carried out without the consent of participants, or of his/her legal representative(s) or guardian(s), if all of the following apply:

  • A serious threat to the prospective participant requires immediate intervention
  • Either no standard efficacious care exists, or the research offers a realistic possibility of direct benefit to the participant in comparison with standard care
  • Either the risk is not greater than that involved in standard efficacious care, or it is clearly justified by the prospect for direct benefits to the participant
  • The prospective participant is unconscious or lacks capacity to understand the risks, methods, and purposes of the research project
  • Authorization from his/her legal representative(s) or guardian(s) cannot be secured in sufficient time, despite diligent and documented efforts to do so
  • No relevant prior directive by the participant is known to exist
4.8
Chapter 3 (Articles 3.7-3.9)
Last content review/update: February 24, 2022

Overview

The MHCTR, the MHCTR2006-No2, the MHCTR-BSQ, GBR-3, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product is complicated by special circumstances. Special circumstances include medical emergencies and when a participant is mentally incapacitated.

Medical Emergencies

As delineated in the G-ConsentPIS, GBR-3, GBR-18, and GBR-4, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of his/her legal representative(s) or guardian(s) should be obtained. If the prior consent of the participant or his/her legal representative(s) or guardian(s) cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or his/her legal representative(s) or guardian(s) should provide consent as soon as possible.

The MHCTR-BSQ amends the MHCTR and creates an exception for minors participating in a trial where urgent treatment is required and prior consent cannot be obtained. This situation also requires the EC to issue its approval beforehand.

Mentally Incapacitated Persons

The MHCTR2006-No2 amends the MHCTR and creates an exception to the general rule in England, Northern Ireland, and Wales that incapacitated adults cannot be included in a clinical trial under medical emergencies. If the treatment to be provided is a matter of urgency and obtaining prior consent is not possible, incapacitated adult participants may be included in the trial once EC approval has been obtained. In Scotland, the provisions of Section 51 of the AIA2000 govern the inclusion of adults lacking capacity in research.

The G-ConsentPIS states that the United Kingdom allows adults not able to consent for themselves to be recruited into clinical trials without prior consent in emergency situations if the following conditions exist:

  • Treatment needs to be given urgently
  • It is also necessary to take urgent action to administer the drug (IMP) for the purposes of the trial
  • It is not reasonably practicable to obtain consent from a legal representative
  • The procedure is approved by an EC
  • Consent is sought from a legal representative as soon as possible
Section 51
Principles of Consent
Schedule 1 (Parts 4 and 5)
4 and Explanatory Note
2 and Explanatory Note
4.8.15
Informed Consent
4.3
5.5.4

Informed Consent > Vulnerable Populations

Last content review/update: August 11, 2022

Overview

As per the G-TCPS2, in all Canadian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The CA-ICH-GCPs characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from not participating. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The CA-ICH-GCPs specify that ethics committees (ECs) (known as Research Ethics Boards in Canada) must pay special attention to protecting participants who are from vulnerable populations. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations.

1.61, 3.1, and 4.8
Chapter 3 (Article 3.9) and Chapter 4 (Article 4.7)
Last content review/update: February 24, 2022

Overview

As per the MHCTR, GBR-3, GBR-4, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. GBR-3 and GBR-4, characterize vulnerable populations as those who are dependent on others and are unable to express their opinion freely or make their own decisions. These participants may include children, persons with mental or physical incapacities, persons with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, prisoners, detainees, refugees, members of a group with a hierarchical structure, such as students, subordinate hospital and laboratory personnel, pharmaceutical industry employees, members of the armed forces, and persons kept in detention.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations.

Schedule 1 (Parts 1, 4, and 5)
1.61, 3.1, and 4.8
4.3
1.3

Informed Consent > Children/Minors

Last content review/update: August 11, 2022

Per CAN-35, because the G-TCPS2 does not specify an age of consent for children, the decision on whether to seek consent from children is based on whether they have the capacity to understand the research and the risks and benefits of their participation. Youth who have not reached the age of majority (either 18 or 19 depending on the province or territory) may still be old enough to provide their own consent. For children who are not sufficiently mature to provide consent but are able to understand the nature of study participation, researchers must obtain the child’s assent in addition to the consent of an authorized third party. The decision of a child not to assent must be respected regardless of whether third-party consent was obtained.

CAN-35 provides the following criteria for determining whether participants can provide their own consent, or whether an authorized third party should be involved:

  • The risk level associated with the research project
  • The legal requirements for age of consent in that jurisdiction
  • The characteristics of the research participant (e.g., maturity level)
  • In certain cases, the topic of the research itself

CAN-35 states that is generally accepted that youth can consent to minimal risk studies at 16 years of age, and that assent should be sought from children beginning at approximately seven (7) years of age. However, it is ultimately up to the researcher to determine whether to obtain assent or consent from children, and to provide the rationale for this decision to the ethics committee (EC) (known as a Research Ethics Board in Canada). Researchers should also consider that within a single research project, some minors may be capable of consenting while others may not. See CAN-35 for additional details regarding obtaining consent from minors.

As per the G-TCPS2 and the CA-ICH-GCPs, when the research participant is a child, the informed consent form (ICF) must be signed by the child’s legal representative(s) and/or guardian(s). All pediatric participants, however, should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the ICF. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

As stated in G-TCPS2, children should only participate in clinical studies when the research objective cannot be achieved with adult participants only. When considering the inclusion of children in research, the investigators and ECs must consider a child’s stage of physical, physiological, psychological, and social development to ensure adequate protections for his/her welfare.

Assent Requirements

Per G-TCPS2 and TCPS2-InterpCnsnt, where a child has some ability to understand the significance of the research, the researcher must ascertain the wishes of that individual with respect to participation. Children—whose decision-making capacity is in the process of development—may be capable of verbally or physically assenting to, or dissenting from, participation in research. While their assent would not be sufficient to permit them to participate in the absence of consent by the child’s legal representative(s) and/or guardian(s), their expression of dissent must be respected.

Further, according to CAN-12, which offers best practices and guidance to researchers and ECs in pediatric research and complements the G-TCPS2, provincial laws in Canada vary as to when a child is presumed to be legally competent to provide informed consent. Some provinces use age while others use a competence-based evaluation.

As per CAN-12, if the pediatric participant has the capacity for assent, his/her affirmative assent is required to participate in a study according to his/her level of development and capacities. When the child develops the legal capacity to provide informed consent or attains the legal age of majority (which depends on the province), researchers should obtain an informed consent. Regarding dissent, CAN-12 states that the researchers must respect the dissent of a child who is capable of understanding.

CAN-35 provides sample assent forms and templates. For more detail and guidance about best practices for research involving pediatric participants, CAN-12.

4.8
Chapter 3 (Article 3.10) and Chapter 4 (Article 4.4)
1
Guidelines III and IV
Consent Process (Key Considerations)
Last content review/update: February 24, 2022

Overview

According to the MHCTR, a minor is an individual under 16 years of age. However, per GBR-4, in situations where the MHCTR does not apply, a minor is an individual under 18 years of age.

As set forth in the MHCTR, the MHCTR2006, the G-ConsentPIS, GBR-4, GBR-9, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), when the research participant is a minor, informed consent should be obtained from his/her legal representative(s) and/or guardian(s). As per GBR-4, legally, the researcher needs only to obtain consent from one (1) person with parental responsibility; however, consent from all legal representative(s) and/or guardians is encouraged.

Additionally, precautions against possible physical and mental harms should be exercised. All pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand. The rights of the minors should also be respected for their voluntary decision to participate in a clinical study.

The MHCTR, the MHCTR2006, GBR-4, and GBR-9, state that a study may only be conducted on minors if several conditions are fulfilled including:

  • An ethics committee (EC), following consultation with pediatric experts, has endorsed the protocol
  • The legal representative(s) and/or guardian(s) has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the minor from the trial at any time
  • No incentives or financial inducements are given to the minor or his/her legal representative(s) and/or guardian(s) except in the event of trial-related injury or loss
  • The trial relates directly to a condition from which the minor suffers, or is of such a nature that it can only be carried out on minors
  • The participant(s) will derive some direct benefit from their participation in the trial
  • The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
  • The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the minor’s stage of development

See the MHCTR, the MHCTR2006, GBR-4, and GBR-9 for detailed requirements. The G-ConsentPIS provides style guidance and suggestions for presenting age-appropriate information in the participant information sheet. Also see GBR-8 for a summary of changes to GBR-9.

Assent Requirements

As delineated in GBR-4, if a minor is deemed competent to give assent to decisions about participation in research, the investigator(s) must obtain that assent in addition to the consent of his/her legal representative(s) and/or guardian(s). If the child does not assent, this should be respected.

Furthermore, GBR-4 states that a minor’s ability to assent or consent is based on his/her ability to understand and assess options, rather than on his/her age. For a minor to be able to have the capacity to make a particular decision, he/she must be able to:

  • Comprehend and retain information material to the decision, especially the consequences of having or not having any intervention
  • Use and weigh this information in a decision-making process
  • Reach and communicate a decision

In addition, GBR-4 specifies that if the competent minor specifically asks for the family not to be involved, and they cannot be persuaded otherwise, his/her privacy should be respected.

Style and Examples & Templates
Part 1 (2) and Schedule 1 (Part 4)
Amendment of Schedule 1 to the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)
4.8.12
5
2.51-2.58

Informed Consent > Pregnant Women, Fetuses & Neonates

Last content review/update: August 11, 2022

As per the G-TCPS2, studies involving women of childbearing age, or who are pregnant, require additional safeguards to ensure that the research assesses the risks to the women and the fetuses.

In accordance with the CA-ICH-GCPs, informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

4.8
Chapter 4 (Article 4.3)
Last content review/update: February 24, 2022

Overview

The G-ConsentPIS states that in studies where there could be harm to an unborn child and/or risk to an infant when breastfeeding, the Participant Information Sheet (PIS) should provide specific advice to potential participants about the risks of becoming pregnant, of fathering a child, or of breastfeeding while taking part in the research.

For women, researchers must give a clear warning to potential participants when there is a risk of harm to an unborn child or risk when breastfeeding. The information should include the need for pregnancy testing, contraceptive requirements, and how to report a pregnancy during the study. The PIS should also provide information about what will happen if a participant becomes pregnant, including whether and how the researcher will monitor the pregnancy. This would include access to the mother's and/or child's notes, and any possible follow up of the child including post-natal examinations.

For men, researchers must provide clear warnings and advice if the research treatment could damage sperm and consequently pose a risk to possible pregnancies. Information concerning the importance of careful contraception and what to do if their partner becomes pregnant is essential. Specific advice for pregnant partners may be needed, including information on any compensation arrangements.

Further, the G-ConsentPIS finds that the risk of harm caused during pregnancy is most likely when recruiting young people to a clinical trial for an investigational medicinal product (CTIMP). In this case, there should be consent from someone over the age of 16, and the following should be done:

  • Discuss the risk of pregnancy, pregnancy testing and the use of appropriate contraception with their parents (or his/her legal representative(s) and/or guardian(s)) during the consent process and with young potential participants as part of the assent process
  • Consider local social beliefs
  • Involve pediatricians and the ethics committee in preliminary discussions if this is a concern
  • Consult young people when designing consent and writing information
  • Respect the young person's autonomy but encourage involvement of the parents
  • Be aware that in CTIMPs, it is the parents of children under 16 who legally provide consent, and this will include consent to pregnancy testing and discussion of contraception
  • Information needs to go beyond "We will do a pregnancy test…" to include what will happen in broad terms

In accordance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

As set forth in GBR-35, any research studies involving women capable of becoming pregnant and breastfeeding women require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. According to GBR-35, the following conditions are required for research to be conducted with this population:

  • Reproductive toxicology studies have been completed and the results support conducting a trial, or, there is a good reason not to conduct the reproductive toxicology studies and/or the risk of pregnancy is minimized (e.g., because she agrees to adhere to a highly effective method of contraception); Women using a hormonal contraceptive, such as “the pill,” should use an alternative method of contraception until the possibility of an interaction with the investigational product has been excluded
  • The female participant is not pregnant according to her menstrual history and a pregnancy test, and is not at risk of becoming pregnant during, and for a specified interval, after the trial
  • The female participant is warned about the potential risks to the developing child should she become pregnant, and she is tested for pregnancy during the trial, as appropriate
  • The female is tested for pregnancy before dosing starts and possibly during the trial, as appropriate
Content – Participant Information Sheet

Informed Consent > Prisoners

Last content review/update: August 11, 2022

According to the G-TCPS2 and the CA-ICH-GCPs, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed, and are given the opportunity to make their own decisions without any interference from a higher authority. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

1.61
Chapter 3 (Article 3.1) and Chapter 4 (Article 4.7)
Last content review/update: February 24, 2022

Overview

Per the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority. The ethics committee must also ensure that the study will be independently monitored to assure the dignity and rights of the prisoners involved in the research.

1.61

Informed Consent > Mentally Impaired

Last content review/update: August 11, 2022

According to the G-TCPS2 and the CA-ICH-GCPs, the ethics committee (EC) (known as Research Ethics Board in Canada) must approve the participation of research participants who are mentally or physically incapable of giving consent.

Per CAN-35, adults with diminished decision-making capacity include:

  • Individuals whose decision-making capacity remains only partially developed, such as those living with permanent cognitive impairment, and
  • Individuals who once were capable of making an autonomous decision regarding consent but whose decision-making capacity is diminishing or fluctuating (e.g., due to cognitive impairment resulting from an injury or disease).

As is the case for any vulnerable population, care must be taken to ensure that adults with diminished decision-making capacity are not inappropriately included in research because of their situation, and neither should they be excluded from participating in research that may benefit them.

The G-TCPS2 indicates that for research involving individuals who lack the capacity, either permanently or temporarily, to decide for themselves whether to participate, the EC must ensure that, as a minimum, the following conditions are met:

  • The researcher involves participants who lack the capacity to decide on their own behalf to the greatest extent possible in the decision-making process.
  • The researcher seeks and maintains consent from the participant’s legal representative(s) or guardian(s) in accordance with the best interests of the persons concerned
  • The legal representative(s) or guardian(s) is not the researcher or any other member of the research team
  • The researcher demonstrates that the research is being carried out for the participant’s direct benefit, or for the benefit of other persons in the same category; if the research does not have the potential for direct benefit to the participant but only for the benefit of the other persons in the same category, the researcher shall demonstrate that the research will expose the participant to only a minimal risk and minimal burden, and demonstrate how the participant’s welfare will be protected throughout the participation in research
  • When authorization for participation was granted by a legal representative(s) or guardian(s), and a participant acquires or regains decision-making capacity during the course of the research, the researcher must promptly seek the participant’s consent as a condition of continuing participation

In general, many of the same principles for obtaining consent for children apply to adults with diminished decision-making capacity. Per CAN-35 and the G-TCPS2, the participant’s legal representative(s) or guardian(s) can provide consent for adults who lack the capacity to decide on their own behalf in accordance with the best interests of the persons concerned. In such cases, participants should still be involved to the greatest extent possible in the decision-making process, and their assent to participate must be obtained if they are capable of expressing their wishes in a meaningful way (whether verbally or physically). Importantly, when authorization for participation was granted by the participant’s legal representative(s) or guardian(s) and a participant acquires or regains decision-making capacity during the course of the research, the researcher must promptly seek the participant’s consent as a condition of continuing participation.

Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

1.61 and 3.1
Chapter 3 (Article 3.7-3.10)
Consent Process (Key Considerations)
Last content review/update: February 24, 2022

Overview

As per the MHCTR and GBR-9, a recognized ethics committee (EC) within the Health Research Authority (HRA), must approve the participation of adult research participants who are incapable by reason of physical and mental capacity to give consent, and must obtain advice from professionals with expertise in handling this patient population.

The MHCTR and the G-ConsentPIS, specify that when a study involves adult participants with mental incapacities, informed consent should be obtained from his/her legal representative (s) and/or guardian(s). This consent should only be provided once the legal representative(s) or guardian(s) has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the participant from the trial at any time. The G-ConsentPIS provides additional country-specific information on legal representative requirements.

As delineated in the MHCTR, a clinical trial of an investigational product may involve participants with mental incapacities under the following conditions:

  • The participant has received information according to his/her capacity of understanding regarding the trial, its risks, and its benefits
  • No incentives or financial inducements are given to the participant or his/her legal representative(s) and/or guardian(s) except in the event of trial-related injury or loss
  • The trial relates directly to a condition from which the participant suffers, or is of such a nature that it can only be carried out on participants with mental incapacities
  • The participant(s) will derive some direct benefit from their participation in the trial, or produce no risk at all
  • The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
  • The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the participant’s stage of development

See the MHCTR, G-ConsentPIS, and GBR-9 for detailed requirements.

Principles of Consent - Adults Who Are Not Able to Consent for Themselves
Part 1 (15), Schedule 1 (Parts 1 and 5)
2.51-2.58

Investigational Products > Definition of Investigational Product

Last content review/update: August 11, 2022

As delineated in the CanadaFDR, the G-GMP-Annex13, and the CA-ICH-GCPs, an investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

1.33
Part C (Division 5 (C.05.001))
5.1
3.0
Last content review/update: February 24, 2022

Overview

As delineated in the MHCTR, the Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, an investigational product (IP), referred to as an investigational medicinal product (IMP) in the United Kingdom (UK), is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

Part 1 (2)
1.3
Terminology (Statutory Definitions Relating to CTIMPs)

Investigational Products > Manufacturing & Import

Last content review/update: August 11, 2022

Manufacturing

As specified in the CanadaFDR, the G-CanadaCTApps, and the CA-ICH-GCPs, Health Canada (HC) authorizes the manufacture of investigational products (IPs) in Canada. HC approves the manufacture of IPs as part of the clinical trial application (CTA) approval. Note that per HCNotice-CA-ICH-GCPs, HC-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. The G-QCM-PharmCTAs provides guidance and templates to assist sponsors in completing the quality portion of the CTA, which in turn, enables HC to assess IP characteristics adequately. The G-GMP-Annex13 requires the sponsor to ensure that IPs for clinical trials are manufactured and imported in accordance with its provisions and with CanadaFDR requirements. Per the G-CanadaCTApps, sponsors must file amendments or notifications to a previously authorized CTA when manufacturing changes are proposed that may affect the quality or safety of the clinical trial drug or biologic supplies.

Import

Per the CanadaFDR and the G-FDR-0100, HC can authorize the sponsor to import an IP. A sponsor who is not based in Canada must have a Canadian representative who is responsible for the import of the IP and demonstrates compliance with the applicable regulatory requirements. This representative should be the sponsor’s senior medical or scientific officer residing in Canada, and is responsible for providing an attestation with respect to the CTA at the time of filing. Per the G-CanadaCTApps, the G-DrugApp, and CAN-4, if clinical trial drugs are to be imported into Canada, the applicable section of CAN-4 should be completed and submitted for each importer in Canada. The G-DrugApp states that Canadian importer(s) must be located within Canada. As additional importers are identified, additional copies of Appendix 1 should be provided to HC.

The G-CanadaCTApps, the G-HlthProdImprtExptReqs, the G-FDR-0100, and CAN-32 state that if a sponsor wants to import a drug into Canada for a clinical trial, he/she must include a copy of HC’s authorization (i.e., the No Objection Letter (NOL)) issued by either the Pharmaceutical Drugs Directorate (PDD) or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) for the applicable trial with the shipment. A copy of this authorization must be provided at the port of entry. The G-HlthProdImprtExptReqs states that drugs without a Drug Identification Number may be imported where authorized for a Canadian clinical trial and a NOL was issued. The G-FDR-0100 further states that if 30 days have passed and the NOL was not issued, specific requests to import IPs should be directed to the Health Product Border Compliance Program at the following email account: hc.hpbcp-pcpsf.sc@canada.ca. Note that a sponsor does not have to submit a CTA for authorization to import an IP used in a Phase IV clinical trial.

Per the G-FDR-0100, if a sponsor plans to send the clinical trial IP(s) directly to each trial site, then the sponsor must also meet the following conditions:

  • Each party, including individual Canadian clinical trial sites, importing drugs directly (i.e., receiving drug shipment directly from outside of Canada) is identified on Appendix 1 of the Drug Submission Application Form (HC/SC 3011 form) (CAN-4) for Phase I-III trials (submitted with the application if known at the time or prior to importation at the site). Appendix 1 may be replicated as many times as necessary to capture all importing parties.
  • Clinical Trial Site Information (CTSI) forms (CAN-6) for each Canadian site conducting the clinical trial are submitted to HC for Phase I-III trials, prior to the start of the study.
  • Systems are in place, when appropriate, to monitor the transportation and storage conditions from the foreign source to the various clinical trial sites across Canada.
  • There is documented accountability of the imported drugs used in clinical trials and distributed to various clinical trial sites located in Canada, including the disposition of drugs returned from the clinical trial sites.
  • A written agreement is in place between the sponsor and the qualified investigator describing their specific responsibilities, and this agreement is available at the clinical trial site.
  • There is evidence that the drugs used in clinical trials conducted in Canada meet Good Manufacturing Practice (GMP) requirements (e.g., certificates of manufacture, certificates of analysis, and/or evidence of approved lot release by a qualified individual).

Per CanadaFDR, the sponsor can make the following changes to the authorized use or importation of drugs if the sponsor notifies HC in writing within 15 days after the date of the change:

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

Other changes must follow the amendment requirements delineated in the CanadaFDR.

See the G-FDR-0100 for additional HC interpretation of the relevant provisions of the CanadaFDR.

2.12 and 5.13
Part C (Divisions 2-5)
2.3 and 2.7
Section # Block D and Appendix 1 Guidance
5.2-5.3 and 5.6
1.0
Importer’s Role, Table 1, and Human Drugs
I, S – Drug Substance, and P – Drug Product
Drug Importation
Appendix 1
Last content review/update: February 24, 2022

Overview

According to the MHCTR, the MHCTR2006, the G-CTApp, and the G-GMP-GDP, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for authorizing the manufacture and import of investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture or importation of any IP to be used in the trial. The sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in GBR-28 to obtain an MIA(IMP) from the MHRA. The MHCTR defines “manufacturing authorization” to include importing and assembly authorizations, as applicable. The G-CTApp states that if an IP is manufactured outside the European Union (EU), the clinical trial application should include an MIA(IMP), importer authorization, and qualified person (QP) declaration on good manufacturing practice (GMP) for each site. The MHRA will approve the manufacture or import of an IP after the clinical trial application has been approved.

As per the MHCTR, the MHCTR2006, the G-GMP-GDP, and GBR-15, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the MIA(IMP) holder must also comply with the GMP guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR, the MHCTR2006, and the G-GMP-GDP, specify that the holder of an MIA(IMP) must always have the services of at least one (1) QP at his/her disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to using in a clinical trial, or prior to releasing for sale and placing on the market. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

In accordance with the G-ImportIMPs, IPs that have been QP-certified in countries on the list of approved countries (initially, EU and European Economic Area (EEA) countries per G-CTApprovedCountries) do not need to be re-certified when importing to the UK. However, the sponsor must require the MIA(IMP) holder to put in place an assurance system to check these IMPs have been certified by a QP in a listed country, before release to the trial. A sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP). IPs coming to Great Britain from Northern Ireland do not require this additional oversight. IPs coming directly to the UK from third-party countries that are not on the list of approved countries will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements. Per the G-ImportIMPsAuth, the verification process described above started as of January 1, 2022. See the G-ImportIMPsAuth, for additional details on the authorizations and procedures. For additional details on what is new from Brexit, see the Scope of Assessment section.

The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119.

Per the G-SubtlAmndmt, for any change to IP manufacturing, importation, or certification relevant to the supply of IPs in an ongoing UK trial, a substantial amendment must be submitted to the MHRA. However, if the sponsor chooses to retain an existing UK release site for the ongoing UK trial but includes an additional EU/EEA site for trials in the EU/EEA only, then no substantial amendment to the MHRA will be required.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Documents to send with your application
Part 1 (2), Part 3 (13), Part 6, Schedule 1 (Part 2), Schedule 3 (Part 2), Schedule 6, and Schedule 7
Amendment of Regulation 13 of the Principal Regulations; Amendment of Regulation 42 of the Principal Regulations; Amendment of Regulation 44 of the Principal Regulations; and Part 2 (Principles based on Articles 2 to 5 of the GCP Directive, Conditions Based on Article 3 of the Directive and Amendment of Schedule 6 to the Principal Regulations)
Annex 2
Application for New Manufacturer’s Authorization for Investigational Medicinal Products MIA (IMP) (Human Use)

Investigational Products > Quality Requirements

Last content review/update: August 11, 2022

Investigator’s Brochure

In accordance with the CanadaFDR and the CA-ICH-GCPs, the sponsor is responsible for providing the investigators with an Investigator’s Brochure (IB). The CanadaFDR and the CA-ICH-GCPs specify that the IB must contain all of the relevant information on the investigational product(s) (IPs), including significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information. The sponsor must ensure that an up-to-date IB is made available to the investigator(s), and the investigator(s) must provide an up-to-date IB to the ethics committee. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

The CanadaFDR and the CA-ICH-GCPs require the IB to provide coverage of the following areas:

  • Physical, chemical, and pharmaceutical properties and formulation parameters
  • Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
  • Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and post-marketing experiences)
  • Summary of data and guidance for the investigator(s)

See Section 7.3 of the CA-ICH-GCPs for detailed content guidelines.

In accordance with the G-CanadaCTApps and CAN-22, the sponsor must submit annually to HC an updated IB, which serves as the annual report, including all safety information and global status. Revisions that are more frequent may be appropriate depending on the stage of development and the generation of relevant new information. As required in G-CanadaNon-eCTD, the annual updated IB should be submitted electronically as a clinical trial application (CTA)-Notification, and include a statement confirming that the protocol and/or informed consent form do not require changes as a result of the updated IB. In all cases, the updated IB should be accompanied by a list of changes that clearly describe the sections that have changed, including a rationale for each change.

Quality Documentation

Pursuant to the CA-ICH-GCPs, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial. As specified in the CA-ICH-GCPs, G-GMP-CAN, and G-GMP-Annex13, the sponsor must ensure that the products are manufactured in accordance with Good Manufacturing Practices (GMPs). The G-GMP-CAN requires a quality management system, incorporating GMPs, to ensure that IPs are of the quality required for their intended use. Per the G-GMP-Annex13, the manufacturer’s quality system should be described in written procedures and available to the sponsor, taking into account GMP principles and guidelines.

2.12, 5.13, 7.3, and 8.2
Part C (Division 5 (C.05.001, C.05.005, and C.05.012))
2.8
5.1, 5.5, and 5.12
4
4
Last content review/update: February 24, 2022

Overview

In accordance with the MHCTR, the MHCTR2006, and GBR-92, the sponsor or his/her designated representative is responsible for complying with the principles of good clinical practice (GCP) as specified in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), and for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor or his/her designated representative should also update the IB as significant new information becomes available.

Investigator's Brochure Content Requirements

As specified in GBR-113, the IB must provide coverage of the following areas:

  • Physical, chemical, and pharmaceutical properties and formulation parameters
  • Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
  • Effects of IMPs in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post marketing experiences)
  • Summary of data and guidance for the investigator(s)
  • Bibliography

See Section 7 of GBR-113 for detailed content guidelines.

As defined in GBR-113, the sponsor is also accountable for supplying the IMP, including the comparator(s) and placebo, if applicable. The MHCTR, the MHCTR2006, the G-GMP-GDP, and GBR-15, also specify that the sponsor or his/her designated representative must ensure that the products are manufactured in accordance with current Good Manufacturing Practice (GMP) guidelines. (See the Product Management section for additional information on IP supply, storage, and handling requirements).

Certificate of Analysis

Per GBR-113, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Part 1 (2), Part 3 (13), Part 6, Schedule 6, and Schedule 7
Insertion of Regulation 3A of the Principal Regulations; Amendment of Regulation 13 of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; Amendment of Regulation 42 of the Principal Regulations, Amendment of Regulation 44 of the Principal Regulations; and Part 2 Principles based on Articles 2 to 5 of the GCP Directive
5.12-5.15, 5.5, and 7
Overview

Investigational Products > Labeling

Last content review/update: August 11, 2022

Investigational product (IP) labeling in Canada must comply with the requirements set forth in the CanadaFDR, the G-CanadaCTApps, the G-GMP-Annex13, and the CA-ICH-GCPs. The CanadaFDR and the G-CanadaCTApps state that for an IP to be used in a clinical trial, it must be properly labeled in both official languages: English and French. The CanadaFDR requires that IPs be packaged and labelled under the supervision of personnel who have had satisfactory technical, academic, and other training. The packager and/or labeler must have written procedures and ensure that the IP is packaged, labelled, and tested in compliance with those procedures. For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

As delineated in the CanadaFDR and the G-GMP-Annex13, the following information must be included on the IP label:

  • A statement indicating that the drug is an investigational drug to be used only by a qualified investigator
  • Name, number, or identifying mark
  • Expiration date
  • Recommended storage conditions
  • Lot number
  • Sponsor’s name and address
  • Protocol code or identification
  • Radiopharmaceutical information, if applicable

With regard to the expiration date, the G-GMP-Annex13 further states that if it becomes necessary to change the expiration date, an additional label should be affixed to the IP. This additional label should state the new expiration date and repeat the batch number. It may be superimposed on the previous expiration date, but for quality control reasons, not on the original batch number. This operation should be performed at an appropriately authorized manufacturing site. However, when justified, it may be performed at the investigational site by or under the supervision of the clinical trial site pharmacist, or other health care professional in accordance with national regulations and with the sponsor’s requirements. Where this is not possible, it may be performed by the clinical trial monitor(s) who should be appropriately trained. The operation should be performed in accordance with good manufacturing practice (GMP) principles, specific and standard operating procedures and under contract, if applicable, and should be checked by a second person. This additional labelling should be properly documented in both the trial documentation and in the packaging records.

For IP packaging, the G-GMP-Annex13 provides the following guidance:

  • The risk of product mix up must be minimized by using appropriate procedures, specialized equipment, and relevant staff training.
  • To prevent errors, particularly when IPs are blinded, use heightened precautions, such as label reconciliation, line clearance, and in-process control checks by appropriately trained staff.
  • The packaging must ensure that the IP remains in good condition during transport and storage at intermediate destinations; any opening or tampering of the outer packaging during transport should be readily discernible.

The G-Storage provides principles and interpretations on the environmental control of clinical trial drugs during storage and transportation, including packaging. See G-Storage for information regarding compliance with the CanadaFDA and the CanadaFDR, as it relates to packaging clinical trial drugs for human use, such as the role of environmental controls, quality risk management, and special considerations for active pharmaceutical ingredients.

In addition, the CA-ICH-GCPs state that the IP must be coded and labeled in a manner that protects the blinding, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

5.13
Part C (Divisions 2 (C.02.006, C.02.011, C.02.015-016) and 5 (C.05.011))
2.8.7
5.11
8.6 and 8.7
Last content review/update: February 24, 2022

Overview

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) must comply with the requirements set forth in the MHCTR, the MHCTR2006, GBR-15, the EU Good Manufacturing Practice Directive (GBR-12), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). Per GBR-12, labeling for IPs must ensure protection of the participant and traceability, to enable identification of the product and trial, and to facilitate proper use of the IP. As specified in GBR-15, for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in GBR-15, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

  • Name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator
  • Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/concentration
  • Batch and/or code number to identify the contents and packaging operation
  • Trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)
  • Trial participant identification number/treatment number and where relevant, the visit number
  • Investigator name (if not already included above)
  • Instructions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)
  • “For clinical trial use only” or similar wording indicating the IP is clinical trial material
  • Storage conditions
  • Expiration date (use by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity
  • “Keep Out of Reach of Children” except when the product is not going to be taken home by participants

As per the MHCTR, a sample of the labeling is required as part of the clinical trial application submission. (See the Submission Content section for detailed clinical trial application submission requirements). Furthermore, according to GBR-15, the IP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Part 1 (2) and Part 7, and Schedule 3, Part 2 (12)
Amendment of Regulation 46 of the Principal Regulations
5.13
Article 15
Annex 13 - Investigational Medicinal Products - Packaging, Labelling, and Table 1

Investigational Products > Product Management

Last content review/update: August 11, 2022

Supply, Storage, and Handling Requirements

Per CanadaFDR, drugs must be manufactured, handled, and stored in accordance with good manufacturing practices (GMPs). As defined in the CA-ICH-GCPs, the sponsor must supply the investigator(s) with the IP(s), including the comparator and placebo, if applicable. The sponsor should not supply the IP(s) until he/she obtains approvals from Health Canada (HC) and the institutional EC. The CA-ICH-GCPs specify that the sponsor must ensure the following:

  • Timely delivery of the IP(s)
  • Records maintained for IP document shipment, receipt, disposition, return, and destruction
  • Written procedures including instructions for IP handling and storage, adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
  • IP product quality and stability over the period of use
  • IP manufactured according to any application of GMPs
  • Proper coding, packaging, and labeling of the IP(s)
  • Acceptable IP handling and storage conditions and shelf-life

Refer to the CA-ICH-GCPs for detailed sponsor-related IP requirements.

The G-Storage provides principles and interpretations on the environmental control of clinical trial drugs during storage and transportation. See G-Storage for information regarding compliance with the CanadaFDA and the CanadaFDR, as it relates to clinical trial drugs for human use, such as the role of environmental controls, quality risk management, and special considerations for active pharmaceutical ingredients.

Record Requirements

As set forth in the CanadaFDR, the G-FDR-0100, and the CanadaFDR1024, the sponsor must record, handle, and store all trial-related information to allow complete and accurate reporting, interpretation, and verification. The CanadaFDR states that the sponsor should maintain all trial-related records for a period of 15 years. Pursuant to CanadaFDR1024, the sponsor must submit requested records to HC within 48 hours if safety concerns arise. Additionally, to facilitate inspection of a site, the sponsor must submit information to HC within seven (7) days of a request.

The G-Storage provides that when contracted parties, such as warehouses or commercial carriers, store or transport drugs, there should be a written agreement that outlines all relevant conditions.

5.5, 5.12, 5.13, 5.14, and 7
Part C (Division 5 (C.05.001, C.05.005, C.05.010, and C.05.012))
Regulatory Impact Analysis Statement
5.1, 5.5, 5.10, and 5.12
Last content review/update: February 24, 2022

Overview

In accordance with the MHCTR, the MHCTR2006, and GBR-92, the sponsor or his/her designated representative is responsible for complying with the principles of good clinical practice (GCP) as specified in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse event data. The sponsor should also update the IB as significant new information becomes available.

Investigational Product Supply, Storage, and Handling Requirements

As defined in the MHCTR and GBR-113, the sponsor must supply the investigator(s)/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until obtaining Medicines and Healthcare Products Regulatory Agency (MHRA) approval and a favorable opinion from a recognized ethics committee (EC).

The sponsor must ensure the following:

  • IP product quality and stability over the period of use
  • IP manufactured according to good manufacturing practice guidance (G-GMP-GDP and GBR-15)
  • Proper coding, packaging and labeling of the IMP(s)
  • IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP
  • Acceptable storage temperatures, conditions, and times for the IP
  • Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
  • Timely delivery of the IP(s)
  • Establishment of management and filing systems for the IPs
  • Sufficient quantities of the IP for the trial

As delineated in GBR-15, IPs should remain under the control of the sponsor until after completion of a two-step procedure: certification by the Qualified Person (QP) and release by the sponsor for use in a clinical trial. Both steps should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. Shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. De-coding arrangements should be available to the appropriate responsible personnel before IPs are shipped to the investigator site. A detailed inventory of the shipments made by the manufacturer or importer should be maintained and include the addressees’ identification.

Refer to the MHCTR and GBR-113 for detailed, sponsor-related IP requirements.

To help ensure the continuity of supply of medicines for clinical trials from January 1, 2021, the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain European Union (EU) regulatory processes for a time-limited period. This recognition is known as “standstill.”

Record Requirements

As per GBR-113, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related pharmacy records are no longer needed. Additionally, the sponsor must ensure sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and should maintain records of batch sample analyses and characteristics.

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request, and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

Part 3 (13 and 15), Part 4 (28), Part 6 (36 and 38), and Schedule 7 (Parts 2 and 3)
Insertion of Regulation 3A of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; and Amendment of Regulation 31 of the Principal Regulations
5.12, 5.13, 5.14, 5.15, 5.5, and 7
Annex 13 – Investigational Medicinal Products – Packaging, Labelling

Specimens > Definition of Specimen

Last content review/update: August 11, 2022

In Canada, a specimen is referred to as “human biological material” or “biological material.” According to the G-TCPS2, human biological materials include tissues, organs, blood, plasma, skin, serum, DNA, RNA, proteins, cells, hair, nail clippings, urine, saliva, and other body fluids. The term also comprises materials related to human reproduction, including embryos, fetuses, fetal tissues, and human reproductive materials. The G-TCPS2 breaks down human biological material further into the following categories: anonymized, anonymous, coded, and identified human biological materials. Refer to the G-TCPS2 for more detailed information on these categories.

In addition, CAN-2 defines biological material as pathogenic and non-pathogenic microorganisms, proteins, and nucleic acids, as well as any biological matter that may contain microorganisms, proteins, nucleic acids, or parts thereof. Examples include, but are not limited to, bacteria, viruses, fungi, prions, toxins, genetically modified organisms, nucleic acids, tissue samples, diagnostic specimens, live vaccines, and isolates of a pathogen (e.g., pure culture, suspension, purified spores).

Chapter 12 and Glossary
Glossary
Last content review/update: February 24, 2022

Overview

The term “specimen” is not referenced within the United Kingdom (UK). However, the following terms are used relating to specimens:

  • Relevant material: As per the UK-HTA, Code-E, GBR-73, and GBR-76, “relevant material” or “human tissue” is any material from a human body, other than gametes, that consists of, or includes, cells. This also includes blood (except where held for transplantation). Hair and nails from living persons are specifically excluded from this definition, as are gametes and embryos outside the body.
  • Bodily material: UK-HTA and GBR-64 defines “bodily material” as material from a human body that consists of, or includes, human cells. Unlike relevant material, this includes gametes, embryos outside the human body, and hair and nails from the body.
  • Tissue: GBR-64 defines “tissue” as any human material (e.g., blood, biopsies, urine) and includes relevant and bodily material.
Glossary
Part 3 (45 and 53)
Bodily Material and Tissues
Definition of Relevant Material

Specimens > Specimen Import & Export

Last content review/update: August 11, 2022

Overview

According to the G-HlthProdImprtExptReqs, Health Canada (HC) does not have jurisdiction over human biological materials to be imported for testing or research purposes. The G-HlthProdImprtExptReqs further states that all blood samples as well as cultures, diagnostic specimens, or research tissue are considered to be potential carriers of human or animal pathogens, and are regulated by the Public Health Agency of Canada (PHAC) and the Canadian Food Inspection Agency (CFIA). Per CAN-24, CAN-2, and CAN-9, the PHAC’s Centre for Biosecurity oversees the licensing process under the authority of the HPTA and the HPTR. The HPTA states that a license must be issued by the Minister that authorizes the import or export of human pathogens or toxins.

Because all human biological materials are potential carriers of human pathogens, the PHAC has categorized these materials by risk group based on risk to the individual/animal and risk to the community. Risk Group 1 consists of microorganisms, nucleic acids, or proteins that are unable or unlikely to cause human or animal disease so they are generally not considered to be pathogens, and are therefore exempt from the HPTA and the HPTR licensing requirements. Risk groups 2 through 4 are considered to be pathogens or toxins with moderate to high individual risk and low to high community risk, and are subject to the HPTA and the HPTR licensing requirements.

As specified in the HPTA, the HPTR, and CAN-2, individuals planning to conduct controlled activities (including producing, possessing, handling, using, storing, providing access to, transferring, disposing of, releasing, abandoning, or importing/exporting) with a human pathogen or toxin, whether imported or domestically acquired, must obtain a license. See CAN-2 and CAN-9 for detailed information and instructions on how to obtain a license for activities associated with Risk Groups 2 through 4.

Blood and blood components for transfusion
Purpose of the Act, Interpretation and Application, Obligation, Prohibitions, and Licenses
Licenses
Chapters 1 and 2
Chapter 21
Last content review/update: February 24, 2022

Overview

As set forth in the UK-HTA, the HTRegs, and GBR-9, the Human Tissue Authority (HTA) regulates the storage and use of specimens (known as “relevant materials” or “human tissue” in the United Kingdom (UK)) from the living, and the removal, storage, use, and licensing of relevant materials/human tissue from the deceased for specified health-related purposes in the UK. The UK-HTA refers to specified purposes as “scheduled purposes.” Per GBR-9, the HTA and the Health Research Authority (HRA) have agreed to collaborative arrangements in a Memorandum of Understanding. See GBR-8 for a summary of changes to GBR-9.

Note that per GBR-9 and GBR-105, an HTA license is not needed for storage of specimens for certain research projects that have been approved by an ethics committee (EC). HTA and the UK Health Departments’ Research Ethics Service (RES) (GBR-62) have agreed that an EC can give generic ethical approval for a research tissue bank’s arrangements for collection, storage, and release of specimens, provided the specimens in the bank are stored on HTA-licensed premises. This approval can extend to specific projects receiving non-identifiable tissue from the bank. The specimens do not then need to be stored on HTA-licensed premises, nor do they need project-specific ethical approval. However, a license is required for specimens stored for which there is no ethical approval (e.g., in large biobanks).

Per the UK-HTA, the G-QAHumTissue, and Code-E, the scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research. Per GBR-52, the Scotland-HTA does not regulate the use of tissue from the living for research.

Human Tissue Authority Requirements

As specified in the UK-HTA, the HTA has jurisdiction regarding the import and export of relevant materials/human tissue, and complies with the Code of Practice on import and export set forth in Code-E. According to the UK-HTA, Code-E, GBR-56, GBR-73, and GBR-52, the import and export of relevant material/human tissue is not in itself a licensable activity under the UK-HTA. However, once the material is imported, storage of this material may be licensable unless it is for a specific research project with ethical approval from an ethics committee (EC). GBR-73 explains that it is preferable for imported human tissue to be stored in a licensed establishment where possible, and if so, there is no requirement for EC approval to undertake research. However, if the premises where the human tissue will be held are not covered by a HTA license, each research project using the human tissue will require EC approval.

If relevant material/human tissue is being imported or exported for an application, the HTRegs specify that this must be carried out under the authority of a license or third-party agreement with an establishment licensed by the HTA to store material for human application. Per G-Tissues-Brexit, because the UK has left the European Union (EU) single market and customs union, there may be regulatory changes to an import/export license to continue to receive tissues and cells for human application from the EU, or send tissues and cells intended for human application to the EU. For details and forthcoming updates, see the G-Tissues-Brexit. For more information about Brexit, see the Scope of Assessment section.

Code-E requires imported material to be procured, used, handled, stored, transported, and disposed of in accordance with the donor’s consent. In addition, due regard should be given to safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as delineated in Code-E. Any individual or organization wishing to import human bodies, body parts, and tissue into England, Wales or Northern Ireland must comply with the guidelines set forth in Code-E.

Exported material should also be procured, used, handled, stored, transported and disposed of, in accordance with the donor’s consent, with due regard for safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as stated in Code-E. This includes providing donors with adequate information upon taking consent, that their samples may be transported as exported samples for use abroad. It is the responsibility of the recipient country to ensure that, prior to export, the material is handled appropriately and that the required country standards have been met.

In addition, the G-QualityBlood lists the quality and safety standards when importing or exporting blood into or from the EU/European Economic Area (EEA). The UK is maintaining the existing quality and safety standards for the collection, testing, processing, storage, and distribution of human blood and blood components. The Medicines and Healthcare Products Regulatory Agency (MHRA) should be consulted before importing or exporting blood or blood components. See the G-QualityBlood for relevant EU quality and safety directives.

Introduction to the Human Tissue Authority Codes of Practice, Licensing – Import and Export, Licensing – HTA Licensing Standards, and Annex A
Glossary/Definitions, Import and Export
Part 1 (6), and Part 2 (7), and Part 3
Section 3
Part 5 (53 (6))
Part 2 (13, 14, 16, 26, and 41)
1 and 3
Import and Export of Tissue
Section 12 and Annex H

Sources > Requirements

(Legislation) Food and Drugs Act (R.S.C., 1985, c. F-27) (CanadaFDA – English and French) (Last Amended May 6, 2021)
Parliament of Canada
(Legislation) Human Pathogens and Toxins Act (S.C. 2009, c. 24) (HPTA) (Last Amended June 21, 2019)
Parliament of Canada
(Legislation) Personal Information Protection and Electronic Documents Act (S.C. 2000, c.5) (PIPEDA) (Last Amended June 21, 2019)
Parliament of Canada
(Legislation) Privacy Act (R.S.C., 1985, P-21) (PrivAct) (Last Amended June 23, 2022)
Parliament of Canada
(Regulation) Food and Drug Regulations, (CRC, c. 870) (CanadaFDR – English and French) (Last Amended June 21, 2022)
Parliament of Canada
(Regulation) Human Pathogens and Toxins Regulations (SOR/2015-44) (HPTR) (Last Amended December 1, 2015)
Parliament of Canada
(Regulation) Regulations Amending the Food and Drug Regulations (1024 - Clinical Trials) (CanadaFDR1024 – English and French) (Effective September 1, 2001)
Parliament of Canada
(Guidance) Annex 13 to the Current Edition of the Good Manufacturing Practices Guidelines - Drugs Used In Clinical Trials (GUI 0036) (G-GMP-Annex13) (Effective December 1, 2009)
Health Canada
(Guidance) Clinical Safety Data Management Definitions and Standards for Expedited Reporting ICH Topic E2A: Guidance for Industry (HC-ICH-E2A) (June 1995)
Health Canada
(Guidance) Filing Submissions Electronically (ElecSubms) (Last Updated September 15, 2022)
Health Products and Food Branch, Health Canada
(Guidance) Good Clinical Practice: Integrated Addendum to E6(R1) ICH Topic E6(R2) (CA-ICH-GCPs) (Effective May 25, 2017)
Health Products and Food Branch, Health Canada
(Guidance) Good Manufacturing Practices Guide for Drug Products (GUI 0001) (G-GMP-CAN) (Effective July 1, 2020)
Health Canada
(Guidance) Guidance Document - Development Safety Update Report (DSUR) - International Conference on Harmonisation (ICH) Topic E2F (G-DSUR) (Effective December 4, 2015)
Health Canada
(Guidance) Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (G-CanadaCTApps) (Last Revised March 17, 2016)
Health Products and Food Branch, Health Canada
(Guidance) Guidance Document: Management of Drug Submissions and Applications (G-MDSA) (Last Updated August 2, 2022)
Health Canada
(Guidance) Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (G-FDR-0100) (August 20, 2019)
Health Canada
(Guidance) Guidance Document: Preparation of Drug Regulatory Activities in the "Non-eCTD Electronic-Only" Format (G-CanadaNon-eCTD) (Last Revised February 3, 2016)
Health Canada
(Guidance) Guidance Document: Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) Format (G-Canada-CTD) (June 22, 2012)
Health Canada
(Guidance) Guidance Document: Preparation of Regulatory Activities in Non-eCTD Format (Non-eCTDformat) (Effective September 7, 2022)
Health Canada
(Guidance) Guidance Document: Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals (G-QCM-PharmCTAs) (Effective June 1, 2009)
Health Products and Food Branch, Health Canada
(Guidance) Guidance for Completing the Drug Submission Application Form (G-DrugApp) (Last Updated March 31, 2021)
Health Canada
(Guidance) Guideline: Increasing Transparency when Presenting Safety Information in the Development Safety Update Report (DSUR): Region-Specific Requirements for Canada and the United Kingdom (G-DSUR-CanUK) (July 6, 2021)
Health Canada
(Guidance) Guidelines for Environmental Control of Drugs During Storage and Transportation (GUI-0069) (G-Storage) (August 24, 2020)
Health Canada
(Guidance) How to Address Material Incidental Findings – Guidance in Applying TCPS2 (2018) Article 3.4 (G-ConsentMatIncFindings) (2019)
Panel on Research Ethics, Government of Canada
(Guidance) Importing and Exporting Health Products for Commercial Use (GUI-0117) (G-HlthProdImprtExptReqs) (Effective December 21, 2020)
Health Products and Food Branch, Health Canada
(Guidance) Policy Statement: Use of Pharmacometrics in Drug Submissions and Clinical Trial Applications (G-Pharmacometrics) (Last Updated March 31, 2021)
Health Canada
(Guidance) Statistical Principles for Clinical Trials ICH Topic E9: Guidance for industry (HC-ICH-E9) (February 10, 2003)
Health Canada
(Guidance) TCPS 2 Interpretations – Consent (TCPS2-InterpCnsnt) (Last Updated August 7, 2018)
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada
(Guidance) TCPS 2 Interpretations – REB Review (TCPS2-InterpReview) (Last Updated May 17, 2021)
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada
(Guidance) Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (G-TCPS2) (December 2018)
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada
(Guidance) Validation Rules for Regulatory Transactions Provided to Health Canada in the Non-eCTD Format (Rules-Non-eCTD) (Version 5.1) (Effective August 1, 2022)
Health Canada
(Notice) E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting – Reminder for Sponsors (HCNotice-E2A) (August 21, 2012)
Health Products and Food Branch, Health Canada
(Notice) Release of ICH E17: Multi-Regional Clinical Trials (HCNotice-ICH-E17) (Last Updated May 9, 2019)
Health Products and Food Branch, Health Canada
(Notice) Release of ICH E6(R2): Good Clinical Practice (HCNotice-CA-ICH-GCPs) (Last Updated November 15, 2019)
Health Canada
(Notice) Release of ICH E9(R1): Defining the Appropriate Estimand for a Clinical Trial/ Sensitivity Analyses (HCNotice-ICH-E9) (Last Updated July 22, 2020)
Health Canada
(Notice) Update to Clinical Trial Site Information Form (HCNotice-CTSIForm) (Last Updated February 23, 2022)
Health Canada
(Notice) Update: Registration and Disclosure of Clinical Trial Information (HCNotice-CTRegDisc) (October 19, 2012)
Health Canada
(Legislation) Adults with Incapacity (Scotland) Act 2000 (AIA2000) (May 9, 2000)
Scottish Parliament, Scotland
(Legislation) Anatomy Act 1984 (Scotland-AnatAct) (May 24, 1984)
UK Parliament
(Legislation) Data Protection Act 2018 (UK-DPAct) (May 23, 2018)
UK Parliament
(Legislation) European Union (Withdrawal Agreement) Act of 2020 (c. 1) (Brexit) (January 30, 2020)
UK Parliament
(Legislation) Human Tissue (Scotland) Act 2006 (Scotland-HTA) (2006)
Scottish Parliament
(Legislation) Human Tissue Act 2004 (UK-HTA) (November 15, 2004)
UK Parliament
(Legislation) Medicines and Medical Devices Act 2021 (MMDAct) (February 11, 2021)
UK Parliament
(Legislation) Mental Capacity Act 2005 (Chapter 9) (MCA2005) (April 7, 2005)
UK Parliament
(Legislation) On the Conclusion of the Agreement on the Withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community (Council Decision (EU) 2020/135) (EUCouncil-Brexit) (January 30, 2020)
EU Council
(Regulation) The Good Laboratory Practice Regulations 1999 (S.I. 1999/3106) (UK-GLPs) (December 14, 1999)
UK Parliament
(Regulation) The Human Tissue (Quality and Safety for Human Application) Regulations 2007 (S.I. 2007/1523) (HTRegs) (May 25, 2007)
UK Parliament
(Regulation) The Medicines (Products for Human Use) (Fees) Regulations 2013 (MPHFR) (Effective March 11, 2013)
Department of Health and Social Care
(Regulation) The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 2019 (No. 744) (MHCTR-EUExit) (Effective January 1, 2021)
Department of Health and Social Care
(Regulation) The Medicines for Human Use (Clinical Trials) Amendment (No.2) Regulations 2006 (S.I. 2006/2984) (MHCTR2006-No2) (December 12, 2006)
Department of Health and Social Care
(Regulation) The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (S.I. 2006/1928) (MHCTR2006) (August 29, 2006)
Department of Health and Social Care, Implements EU Good Clinical Practice Directive 2005/28/EC
(Regulation) The Medicines for Human Use (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 (S.I. 2008/941) (MHCTR-BSQ) (May 1, 2008)
Department of Health and Social Care
(Regulation) The Medicines for Human Use (Clinical Trials) Regulations 2004 (S.I. 2004/1031) (MHCTR) (May 1, 2004)
Department of Health and Social Care, Implements EU Clinical Trials Directive 2001/20/EC
(Regulation) UK General Data Protection Regulation (UK-GDPR) (Effective January 1, 2021)
UK Parliament
(Guidance) Authorizations and Procedures Required for Importing Investigational Medicinal Products to Great Britain from Approved Countries (G-ImportIMPsAuth) (Last Updated December 22, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Clinical Trials for Medicines: Apply for Authorisation in the UK (G-CTApp) (Last Updated January 7, 2022)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Clinical Trials for Medicines: Manage Your Authorisation, Report Safety Issues (G-CTAuth) (Last Updated February 7, 2022)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Code A: Guiding Principles and the Fundamental Principle of Consent (Code-A) (May 20, 2020)
Human Tissue Authority
(Guidance) Code E: Research - Code of Practice and Standards (Code-E) (April 2017)
Human Tissue Authority
(Guidance) Completed Pediatric Studies - Submission, Processing, and Assessment (G-PIPs) (December 31, 2020)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Consent and Participant Information Guidance (G-ConsentPIS) (Version 11) (March 2021)
Medical Research Council, Health Research Authority
(Guidance) GDPR Guidance for Researchers and Study Coordinators (G-GDPR) (Current as of February 23, 2022)
Health Research Authority
(Guidance) Good Manufacturing Practice and Good Distribution Practice (G-GMP-GDP) (Last Updated December 27, 2020)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Governance Arrangements for Research Ethics Committees: 2020 Edition (GAfREC) (Version 2.1) (Last Updated July 20, 2021)
UK Health Departments
(Guidance) Guidance for Health and Social Care Researchers at the End of the Transition Period (G-AfterTransition) (Last Updated December 30, 2021)
Health Research Authority
(Guidance) Guidance for the Notification of Serious Breaches of GCP or the Trial Protocol (G-MHRA-SeriousBreaches) (Version 6) (July 8, 2020)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Guidance on Submitting Clinical Trial Safety Reports (G-SftyRpts) (December 31, 2020)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Guidance on Substantial Amendments to a Clinical Trial (G-SubtlAmndmt) (December 31, 2020)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Guidance on the Licensing of Biosimilar Products (G-Biosimilars) (May 6, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Guideline on How to Increase Transparency when Presenting Safety Information in the Development Safety Update Report (DSUR): Region-specific Requirements for Canada and the United Kingdom (DSUR-UK_Canada) (July 6, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) HTA Guide to Quality and Safety Assurance for Human Tissues and Cells for Patient Treatment (G-QAHumTissue) (January 2021)
Human Tissue Authority
(Guidance) Importing Investigational Medicinal Products into Great Britain from Approved Countries (G-ImportIMPs) (Last Updated December 22, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) List of Approved Countries for Clinical Trials and Investigational Medicinal Products (G-CTApprovedCountries) (Last Updated December 22, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Make a Payment to MHRA (G-MHRAPaymt) (Last Updated September 15, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) On-Site Access to Electronic Health Records by Sponsor Representatives in Clinical Trials (G-EHRAccess) (September 8, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Oversight and Monitoring of Investigational Medical Product Trials (G-Ovrsight) (January 28, 2022)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Procedures for UK Paediatric Investigation Plan (PIPs) (G-PIPsProcess) (December 31, 2020)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Quality and Safety of Human Blood and Blood Products (G-QualityBlood) (Last Updated May 27, 2021)
Department of Health and Social Care
(Guidance) Register to Make Submissions to the MHRA (G-MHRASubmiss) (Last Updated May 4, 2021)
Medicines and Healthcare Products Regulatory Agency, Department of Health and Social Care
(Guidance) Risk-Adapted Approach to Clinical Trials and Risk Assessments (G-RiskAssmt) (January 28, 2022)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Statutory Guidance: Current MHRA Fees (G-MHRAFees) (Last Updated September 5, 2022)
Medicines and Healthcare Products Regulatory Agency
(Guidance) Step-by-step Guide to Using IRAS for Combined Review (G-IRASCombRev) (Last Updated February 1, 2022)
Health Research Authority
(Guidance) Supplying Investigational Medicinal Products to Northern Ireland (G-IPsNIreland) (Last Updated December 22, 2021)
Medicines and Healthcare Products Regulatory Agency
(Guidance) UK Transition Guidance (G-Tissues-Brexit) (Last Updated September 13, 2021)
Human Tissue Authority
(Correspondence) Letter to Medicines and Medical Product Suppliers: 17 November 2020 (BrexitLtr-IPs) (Last Updated December 28, 2020)
Department of Health and Social Care
(International Agreement) Agreement on the Withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community (WithdrlAgrmt) (December 18, 2020)
European Union, European Atomic Energy Community, and the United Kingdom of Great Britain and Northern Ireland

Sources > Additional Resources

(Document) Best Practices for Health Research Involving Children and Adolescents: Genetic, Pharmaceutical and Longitudinal Studies (CAN-12) (2012)
Canadian Institutes of Health Research, Government of Canada; Centre of Genomics and Policy, McGill University; and Maternal Infant Child and Youth Research Network
(Document) Canadian Biosafety Handbook (CAN-9) (Second Edition) (May 26, 2016)
Government of Canada
(Document) Canadian Biosafety Standard (CBS) (CAN-2) (Second Edition) (March 11, 2015)
Government of Canada
(Document) Research Ethics Board’s Operational Policy Framework: Ethics Review of Research Involving Human Subjects (CAN-13) (April 1, 2010)
Health Canada
(Document) University of Calgary CHREB Administration Fee for Industry Sponsored Protocols (CAN-3) (January 1, 2021)
University of Calgary, Research Services, Calgary, Canada
(International Guidance) Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials, E9 (R1) (CAN-39) (Step 4 Version) (November 20, 2019)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) General Considerations for Clinical Studies E8(R1) (CAN-49) (October 6, 2021)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) General Principles for Planning and Design of Multi-Regional Clinical Trials, E17 (CAN-40) (Step 4 Version) (November 16, 2017)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) ICH E8(R1): General Considerations for Clinical Studies (CAN-48) (October 6, 2021)
Health Canada
(Not Available Online) NIAID Communication with Health Canada (June 2022) (CAN-44)
(Webpage) Biologic and Radiopharmaceutical Drugs Directorate (CAN-17) (Last Updated June 23, 2021)
Health Products and Food Branch, Health Canada
(Webpage) Canadian Clinical Trials Asset Map (CCTAM) (CAN-26) (Current as of August 11, 2022)
Canadian Clinical Trials Coordinating Centre
(Webpage) Clinical Trials - Background (CAN-31) (Last Updated July 11, 2006)
Health Canada
(Webpage) Clinical Trials Drug Importation Frequently Asked Questions (CAN-32) (Last Updated July 11, 2006)
Health Products and Food Branch, Health Canada
(Webpage) ClinicalTrials.gov (CAN-45) (Current as of August 11, 2022)
US National Library of Medicine
(Webpage) Common Electronic Submissions Gateway (CAN-25) (Last Updated May 23, 2014)
Health Canada
(Webpage) Filing of Clinical Trials Frequently Asked Questions (CAN-33) (Last Updated February 21, 2008)
Health Canada
(Webpage) Forms: Applications and Submissions for Drug Products (CAN-19) (Last Updated July 28, 2022)
Health Canada
(Webpage) Health Portfolio (CAN-29) (Last Updated August 8, 2017)
Government of Canada
(Webpage) Health Products and Food Branch (CAN-16) (Last Updated June 24, 2022)
Health Products and Food Branch, Health Canada
(Webpage) How Drugs are Reviewed in Canada (CAN-23) (Last Updated February 12, 2015)
Health Canada
(Webpage) Instructions for Completing the Clinical Trial Site Information Form (CAN-30) (Last Updated June 15, 2022)
Health Canada
(Webpage) ISRCTN Registry (CAN-46) (Current as of August 11, 2022)
ISRCTN Registry
(Webpage) Office of the Privacy Commissioner of Canada (CAN-42) (Last Updated July 5, 2022)
Office of Privacy Commissioner of Canada
(Webpage) Panel on Research Ethics – Navigating the Ethics of Human Research (CAN-14) (Last Updated February 10, 2022)
Panel on Research Ethics, Government of Canada
(Webpage) Pharmaceutical Drugs Directorate (CAN-18) (Last Updated May 2, 2022)
Health Products and Food Branch, Health Canada
(Webpage) Post-Authorization Requirements (CAN-22) (Last Updated February 5, 2009)
Health Canada
(Webpage) Provincial and Territorial Privacy Laws and Oversight (CAN-43) (Last Updated June 11, 2020)
Office of Privacy Commissioner of Canada
(Webpage) Public Health Agency of Canada – Licensing Program (CAN-24) (Last Updated April 28, 2020)
Public Health Agency of Canada
(Webpage) REB Review Fees (CAN-1) (Effective January 1, 2022)
University of Alberta
(Webpage) Regulatory Innovation for Health Products: Overview (CAN-41) (Last Updated February 23, 2022)
Health Canada
(Webpage) Research Ethics Board: Overview of the Health Canada and Public Health Agency of Canada REB (CAN-35) (Last Updated March 28, 2022)
Health Canada
(Webpage) What is the Canadian Clinical Trials Asset Map? (CAN-27) (Current as of August 11, 2022)
Canadian Clinical Trials Coordinating Centre
(Document) Applying a Proportionate Approach to the Process of Seeking Consent (GBR-31) (Version 1.02) (May 3, 2018)
Health Research Authority
(Document) Consent and Confidentiality in Clinical Genetic Practice: Guidance on Genetic Testing and Sharing Genetic Information: A Report of the Joint Committee on Medical Genetics (GBR-37) (Second Edition) (September 2011)
Royal College of Physicians, Royal College of Pathologists, and The British Society for Human Genetics
(Document) Explanatory Memorandum to the Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 2019 (No. 744) (GBR-115) (2019)
Department of Health and Social Care
(Document) Governance Review Check Guidelines (GBR-29) (Version 5.0) (November 21, 2021)
Health Research Authority
(Document) Guidelines for Phase I Clinical Trials (2018 Edition) (GBR-35) (May 29, 2018)
Association for the British Pharmaceutical Industry, UK
(Document) Insurance and Compensation in the Event of Injury in Phase I Clinical Trials (GBR-33) (June 27, 2012)
Association for the British Pharmaceutical Industry, BioIndustry Association, Clinical Contract Research Association
(Document) Joint Statement on Seeking Consent by Electronic Methods (GBR-6) (Version 1.2) (September 2018)
Medicines and Healthcare Products Regulatory Agency (MHRA), Health Research Authority
(Document) MRC Ethics Guide – Medical Research Involving Children (GBR-4) (2004)
Medical Research Council, UK
(Document) MRC Ethics Guide 2007 – Medical Research Involving Adults Who Cannot Consent (GBR-3) (2007)
Medical Research Council, UK
(Document) MRC/DH Joint Project to Codify Good Practice in Publicly-Funded UK Clinical Trials with Medicines - Workstream 6: Pharmacovigilance (GBR-1) (July 2012)
Health Research Authority
(Document) Nagoya Protocol on Access and Benefit-sharing (GBR-5) (2011)
Convention on Biological Diversity, United Nations
(Document) RES SOPs (Version 7.5.1) Summary of Changes (GBR-8) (August 2021)
UK Health Departments’ Research Ethics Service, Health Research Authority
(Document) Research and the Human Tissue Act 2004 - Consent (GBR-59) (Version 3) (January 2019)
Medical Research Council
(Document) SOP – Submitting a CTA Application to the MHRA (GBR-17) (Version 13.0) (Effective November 2, 2021)
Imperial College London, National Health Service
(Document) Sponsorship Principles (Research and Development Forum) (GBR-2) (Version 1.0) (February 2021)
Research and Development Forum, National Health Service
(Document) Standard Operating Procedures for Research Ethics Committees (GBR-9) (Version 7.5.1) (August 2021)
UK Health Departments’ Research Ethics Service, Health Research Authority
(Document) Summary of Legal Requirements for Research with Human Tissues in Scotland (GBR-52) (V2) (June 2016)
Medical Research Council
(Document) User Reference Guide – Gaining Access to MHRA Submissions (GBR-11) (Date Unavailable)
Medicines and Healthcare Products Regulatory Agency
(Document) Clinical Trials Facilitation Group (CTFG) Q&A document – Reference Safety Information (GBR-30) (November 2017)
Heads of Medicines Agencies (in cooperation with the European Medicines Agency and the European Commission)
(International Guidance) Commission Directive 2003/94/EC of 8 October 2003 Laying Down the Principles and Guidelines of Good Manufacturing Practice in Respect of Medicinal Products for Human Use and Investigational Medicinal Products for Human Use (GBR-12) (EU Good Manufacturing Practice Directive) (October 8, 2003)
European Commission, European Parliament and European Council
(International Guidance) EudraLex - Volume 4 - Good Manufacturing Practice (GMP) Guidelines (GBR-15) (Date Varies by Guidance)
European Commission
(International Guidance) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) (Step 4 Version) (GBR-113) (November 9, 2016)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC (GBR-21) (EU Clinical Trials Regulation) (April 16, 2014)
European Parliament and Council
(Not Available Online) NIAID Communication with Health Research Authority (December 2021) (GBR-118)
(Webpage) Applying to a Research Ethics Committee (GBR-68) (Last Updated August 2, 2021)
Health Research Authority
(Webpage) Brexit Guidance (GBR-60) (Current as of March 28, 2022)
Government of United Kingdom
(Webpage) Clinical Trials - Regulation EU No 536/2014 (GBR-86) (Current as of February 23, 2022)
European Commission
(Webpage) Clinical Trials in the European Union (GBR-121) (Current as of February 23, 2022)
European Union
(Webpage) Clinical Trials Regulation (GBR-54) (Current as of February 23, 2022)
European Medicines Agency
(Webpage) Clinical Trials Toolkit – Routemap (GBR-18) (Current as of February 23, 2022)
Medicines and Healthcare Products Regulatory Agency, Department of Health and Social Care
(Webpage) ClinicalTrials.gov (GBR-49) (Current as of February 23, 2022)
U.S. National Library of Medicine
(Webpage) Combined Review (GBR-72) (Last Updated February 23, 2022)
Health Research Authority
(Webpage) Contact MHRA (GBR-58) (Last Updated February 14, 2022)
Medicines and Healthcare Products Regulatory Agency
(Webpage) Country Profile: United Kingdom (GBR-48) (Current as of February 23, 2022)
Access and Benefit-sharing Clearing-house, Convention on Biological Diversity, United Nations
(Webpage) eSUSAR (GBR-50) (Current as of February 23, 2022)
Medicines and Healthcare Products Regulatory Agency
(Webpage) EudraCT – European Union Drug Regulating Authorities Clinical Trials Database (GBR-87) (Version 10.5.0.0) (Last Updated December 15, 2021)
European Medicines Agency
(Webpage) Examples of Substantial and Non-Substantial Amendments (GBR-98) (Last Updated March 25, 2021)
Health Research Authority
(Webpage) Fast-track Research Ethics Review (GBR-116) (Last Updated February 22, 2022)
Health Research Authority
(Webpage) Four Nations Policy Leads Group (GBR-97) (Last Updated September 20, 2021)
Health Research Authority
(Webpage) Good Clinical Practice for Clinical Trials (GBR-92) (Last Updated January 28, 2022)
Medicines and Healthcare Products Regulatory Agency
(Webpage) Guide to the UK General Data Protection Regulation (UK GDPR) (GBR-89) (Current as of January 1, 2021)
Information Commissioner’s Office
(Webpage) Health Research Authority - Glossary (GBR-64) (Current as of February 23, 2022)
Health Research Authority
(Webpage) Help - Using IRAS - New Users (GBR-106) (Current as of February 23, 2022)
Health Research Authority
(Webpage) HRA Approval (GBR-67) (Last Updated November 22, 2021)
Health Research Authority
(Webpage) Human Tissue Act 2004 (GBR-75) (Last Updated November 20, 2020)
Human Tissue Authority
(Webpage) Informing Participants and Seeking Consent (GBR-69) (Last Updated September 4, 2019)
Health Research Authority
(Webpage) Integrated Research Application System (IRAS) Login Page (GBR-78) (Version 6.1) (Last Updated January 4, 2022)
Health Research Authority
(Webpage) Integrated Research Application System (IRAS): Collated Question-Specific Guidance for NHS REC Form (GBR-77) (Version 14) (Last Updated July 27, 2017)
Health Research Authority
(Webpage) International Standardized Randomized Controlled Trial Number (ISRCTN) Registry (GBR-47) (Current as of February 23, 2022)
BioMed Central
(Webpage) IRAS - Templates for Supporting Documents (GBR-107) (Last Updated February 10, 2022)
Health Research Authority, Department of Health and Social Care
(Webpage) IRAS Development Questions and Answers (GBR-122) (Last Updated February 15, 2022)
Health Research Authority
(Webpage) Keep Data Flowing at the End of the UK’s Transition out of the EU (GBR-7) (December 3, 2020)
Information Commissioner’s Office
(Webpage) Launch of the UK Local Information Pack: Supporting the Set-up of NHS/HSC Research in the UK (GBR-63) (Last Updated June 4, 2019)
Health Research Authority
(Webpage) MHRA - About Us (GBR-57) (Current as of February 23, 2022)
Medicines and Healthcare Products Regulatory Agency
(Webpage) MHRA Account Request – MHRA Submissions (GBR-13) (Current as of February 23, 2022)
Medicines and Healthcare Products Regulatory Agency
(Webpage) Model Agreements (GBR-70) (Last Updated July 31, 2019)
Health Research Authority
(Webpage) Online Booking Service (GBR-95) (Last Updated December 24, 2021)
Health Research Authority
(Webpage) Progress Reports (GBR-65) (Last Updated June 7, 2021)
Health Research Authority
(Webpage) Relevant Material Under the Human Tissue Act 2004 (GBR-76) (Current as of February 23, 2022)
Health Tissue Authority
(Webpage) Research Ethics Committees Overview (GBR-111) (Last Updated February 4, 2020)
Health Research Authority
(Webpage) Research Ethics Service (GBR-62) (Last Updated November 8, 2021)
Health Research Authority
(Webpage) Research FAQs (GBR-105) (Last Updated April 20, 2021)
Human Tissue Authority
(Webpage) Research Registration and Research Project Identifiers (GBR-102) (Last Updated January 31, 2022)
Health Research Authority, Department of Health and Social Care
(Webpage) Research Transparency (GBR-55) (Last Updated October 11, 2021)
Health Research Authority
(Webpage) Roles and Responsibilities (GBR-103) (Last Updated May 26, 2021)
Health Research Authority
(Webpage) Safety Reporting (GBR-99) (Last Updated September 6, 2021)
Health Research Authority
(Webpage) Staying Connected with Your Participants (GBR-117) (Current as of February 23, 2022)
Parkinson’s UK
(Webpage) Templates: Recommended Wording to Help You Comply with GDPR (GBR-100) (Current as of February 23, 2022)
Health Research Authority
(Webpage) The Northern Ireland Protocol - Details of the agreement reached by Withdrawal Agreement Joint Committee regarding the implementation of the Northern Ireland Protocol (GBR-119) (Last Updated January 5, 2021)
United Kingdom Cabinet Office
(Webpage) UK Policy Framework for Health and Social Care Research (GBR-101) (Last Updated April 29, 2022)
Health Research Authority (England), the Department of Health and Social Care (Northern Ireland), the Scottish Government Health and Social Care Directorates, and the Department for Health and Social Services (Wales)
(Webpage) UK Transition Licensing FAQs (GBR-56) (Last Updated September 13, 2021)
Human Tissue Authority
(Webpage) Use of Human Tissue in Research (GBR-73) (Last Updated November 16, 2021)
Health Research Authority
(Webpage) What Approvals and Decisions Do I Need? (GBR-66) (Current as of February 23, 2022)
Health Research Authority
(Webpage) Writing a Plain Language (Lay) Summary of Your Research Findings (GBR-120) (Last Updated November 9, 2021)
Health Research Authority

Sources > Forms

(Form) Adverse Drug Reactions (ADRs) for Clinical Trials – Expedited Reporting Summary Form (CAN-5) (Date Unavailable)
Health Canada
(Form) Check list for Submitting Requested Development Safety Update Reports (DSUR) in Electronic Format (CAN-38) (Date Unavailable)
Health Canada
(Form) CIOMS Form I (CAN-7) (Date Unavailable)
Council for International Organizations of Medical Sciences
(Form) Clinical Trial Site Information Form (CAN-6) (Ver.21.12.21) (Effective January 2, 2020)
Health Canada
(Form) Health Canada 3011: Drug Submission Application Form for Human, Veterinary or Disinfectant Drugs and Clinical Trial Application/Attestation (CAN-4) (Version 5.03) (Last Updated March 2, 2022)
Health Canada
(Form) Qualified Investigator Undertaking (CAN-37) (March 23, 2022)
Health Canada
(Form) Research Ethics Board Attestation (CAN-8) (Last Updated March 2, 2022)
Health Products and Food Branch, Health Canada
(Form) Clinical Trial of an Investigational Medicinal Product (CTIMP), Annual Progress Report to Research Ethics Committee (GBR-27) (Version 4.5) (Last Updated January 2021)
Health Research Authority
(Form) Declaration of the End of Trial Form (GBR-24) (Revision 3, June 2010) (EudraLex, Volume 10, Clinical Trials Guidelines)
European Commission
(Form) Medicines: Application Forms for a Manufacturer License (GBR-28) (May 14, 2020)
Medicines and Healthcare Products Regulatory Agency
(Form) Pay MHRA Invoices (GBR-26) (Current as of February 23, 2022)
Medicines and Healthcare Products Regulatory Agency
(Form) Submit your Final Report - Health Research Authority (GBR-20) (Current as of February 23, 2022)
Health Research Authority
(Form) Substantial Amendment Notification Form (GBR-25) (Revision 3, June 2010) (EudraLex, Volume 10, Clinical Trials Guidelines)
European Commission
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This message was reviewed on November 30, 2022