Clinical Research Regulation For Canada and India

Last content review/update: June 16, 2023

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; and “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
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

The CanadaFDR and the G-CanadaCTApps also delineate that a clinical trial application-amendment (CTA-A) is required for proposed changes to a previously authorized study when the changes to clinical trial drug supplies affect the quality or safety of the drug, or when the changes to an authorized protocol alter the risk to clinical trial participants, or both. CTA-As must be authorized by HC prior to implementation of the changes. However, if the sponsor is required to immediately implement changes because the clinical trial or the use of the clinical trial drug endangers the health of participants or other persons, the sponsor may immediately make the amendment without prior review by HC. Sponsors must notify HC of this change, provide the relevant rationale in support of the immediate implementation, and file a CTA-A that clearly identifies the change and rationale for immediate implementation of the change within 15 days after the amendment implementation date. In addition, sponsors may make the following changes immediately if it 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; or a change to the protocol that does not alter the risk to the health of a participant.

Per the CanadaFDR, HC will suspend the authorization to sell or import a drug for clinical trial purposes if it has reasonable grounds to believe that:

The sponsor has contravened any relevant laws or regulations
Any information submitted in respect of the drug or clinical trial is false or misleading
The sponsor has failed to comply with good clinical practices
The sponsor has failed to provide information or samples as required by the regulation

See the CanadaFDR for additional details on HC’s suspension and cancellation responsibilities.

Clinical Trial Site Information form

What is the Health Products and Food Branch?

1.2, 2.1, 2.3-2.7, and Appendix 1

5.1, 5.2, 5.5, and 5.6

2 and Part II (Section 30 (1.2))

Part C (Division 5 (C.05.001, C.05.002, C.05.005-.008, and C.05.016-.017))

Last content review/update: February 2, 2023

Overview

In accordance with the 2019-CTRules and the Hdbk-ClinTrial, the Drugs Controller General of India (DCGI), who heads the Central Drugs Standard Control Organization (CDSCO), is responsible for reviewing and approving clinical trial applications for all new drugs, investigational new drugs (INDs), and imported drugs to be registered in India. Additionally, per the 2019-CTRules, the G-ICMR, and IND-31, the DCGI and a DCGI-registered ethics committee (EC) must approve a clinical trial application prior to the sponsor (also known as applicant) initiating the trial, except in the case of non-regulatory academic/research clinical trials that only require EC approval. Refer to the Scope of Review section for detailed information on non-regulatory academic/research clinical requirements. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

As per the 2019-CTRules and the Hdbk-ClinTrial, the scope of the DCGI assessment includes a review of applications for IND and new drug clinical trials, global clinical trials (GCTs), and post marketing studies (Phases I-IV). Per Notice18Feb20, which clarifies information provided in IND-31, the 2019-CTRules are only applicable to new drugs and investigational new drugs. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2019-CTRules defines a “new drug” as:

A drug, including active pharmaceutical ingredients or phytopharmaceutical drugs, that has not been used in the country to any significant extent
A drug that has already been approved by the DCGI and is now proposed to be marketed with modified or new claims
A fixed dose combination of two (2) or more drugs, individually approved for earlier specific claims, and which are now proposed to be combined for the first time in a fixed ratio, or, if the ratio of ingredients in an already marketed combination is proposed to be changed
A modified or sustained release form of a drug, or novel drug delivery system of any drug approved by the DCGI
A vaccine, recombinant Deoxyribonucleic Acid (r-DNA)-derived product, living modified organism, monoclonal antibody, cell, or stem cell derived product, gene therapeutic product, or xenografts intended to be used as a drug

Per the 2019-CTRules and IND-31, the above listed drugs, excluding the modified/sustained drug forms and biological drug products, will be deemed new for four (4) years from the date of first approval. The modified/sustained drug forms and biological products including vaccines should always be viewed as new drugs. See also IND-6 for additional information on the revised definition of “new drug” under the 2019-CTRules.

The 2019-CTRules defines an IND as a new chemical or biological entity or a product having therapeutic indication but that has never been tested on human beings, and as also noted in IND-31, has not been approved as a drug for marketing in any country.

In addition, according to IND-31, the DCGI review and approval process may be conducted in parallel with the institutional or independent EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm that the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (See the Scope of Review section for more information.)

Clinical Trial Review Process

As set forth in the 2019-CTRules and the Hdbk-ClinTrial, the DCGI is responsible for reviewing and approving clinical drug applications. The evaluation timeline is dependent upon whether the investigational drugs under review are developed outside India, or discovered, researched, and manufactured in India. (Refer to the Timeline of Review section for detailed CDSCO timeline information.)

Per the Hdbk-ClinTrial, upon receipt of an application (via Form CT-04 which is found in the 2019-CTRules), a CDSCO official is responsible for conducting the initial administrative review. If the application is deemed complete, the official forwards the application along with a summary of his/her evaluation and a statement referring the proposal to a Subject Expert Committee (SEC) for further technical review. If the proposal is not accepted by the SEC, the sponsor may request additional consideration of the proposal by the Technical Committee. Otherwise, only the SEC’s recommendations are required for the DCGI (CDSCO) to issue a final decision to the Technical or Apex Committee.

Per the Hdbk-ClinTrial, SECs are usually comprised of six (6) experts representing various therapeutic areas, including pharmacologists/clinical pharmacologists, and medical specialists. However, Order13Jan20, issued in accordance with the 2019-CTRules, indicates that SECs will be comprised of eight (8) medical experts, specifically one (1) pharmacologist and seven (7) medical specialists. Per the Hdbk-ClinTrial, SECs are responsible for advising CDSCO with in-depth evaluations of non-clinical data (including pharmacological and toxicological data) and clinical trial data (Phases I-IV) provided by the sponsors for approval. The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with specialization in relevant fields to evaluate scientific and technical drug-related issues.

Additionally, per Order13Jan20, SECs will evaluate and advise the DCGI on proposals in various categories for the approval of new drug and clinical trial applications. These include the following: new drug substances of chemical and biological origin including vaccines and r-DNA derived products; subsequent approval of new drug and biological products including vaccines and r-DNA derived products already approved in the country; global clinical trials; fixed dose combinations of two (2) or more drugs to be introduced for the first time in the country; causality analysis, drug safety, or any other technical matter requiring expert advice in the opinion of the Ministry of Health and Family Welfare (MOHFW) or the DCGI. See Order13Jan20 for the complete terms of reference required to constitute SECs.

Once an SEC has completed its review, the Hdbk-ClinTrial indicates that the committee sends its comments via email to CDSCO. CDSCO will then compile any written SEC comments requiring sponsor clarification or modification and sends this feedback to the sponsor. The sponsor must submit a written reply to CDSCO, which is also sent to the SEC for review.

Following receipt of the sponsor’s response, the DCGI (CDSCO) will issue a final decision by official communication (permission, rejection, or resubmission) to the Technical or Apex Committee. In the case of a sponsor’s request for reconsideration, CDSCO will review the resubmitted application and send it to the SEC again, or, to the Technical Committee per the sponsor’s request. Following the SEC’s review, the DCGI (CDSCO) will send a final decision to the Technical or Apex Committee. If CDSCO rejects the reconsideration request, the agency will send a letter to the sponsor to communicate this decision. Refer to the Hdbk-ClinTrial for additional timeline information.

Per the 2022-CTRules-3rdAmdt, which amends the 2019-CTRules, upon obtaining approval from the DCGI, the sponsor must notify CDSCO via Form CT-06A (see 2022-CTRules-3rdAmdt) prior to initiating the clinical trial. The DCGI will then record the information provided on this form and it will become part of the official record known as the approval of the DCGI. The DCGI grants permission to initiate a clinical trial via either Form CT-06 (see 2019-CTRules) or as an automatic approval via Form CT-4A (see 2019-CTRules). 2022-CTRules-3rdAmdt further states that when the DCGI approves a clinical trial of a new drug already approved outside India per the 2019-CTRules, the sponsor must also notify CDSCO via Form CT-06A, and this record will become part of the official record known as the guaranteed approval of the DCGI.

Per the 2019-CTRules, the DCGI’s permission to initiate a clinical trial granted via either Form CT-06 or as an automatic approval via Form CT-4A will remain valid for two (2) years from the date of its issue, unless extended by the DCGI as noted in the 2019-CTRules and IND-31.

In addition, per the 2019-CTRules, an investigator should not implement any deviations from or changes to the protocol without the sponsor’s agreement and after obtaining the EC’s prior review and documented approval or favorable opinion of the amendment. All protocol amendments should be submitted to the DCGI in writing along with the EC approval letter. Similarly, the G-ICMR indicates that the EC must review and approve any protocol amendments, major deviations, or violations prior to those changes being implemented.

The 2019-CTRules explains that the exception to this requirement is when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature. In this case, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should be notified of administrative or logistical changes or minor amendments in the protocol within 30 days.

The Hdbk-ClinTrial and the 2019-CTRules also note that application reviews should be based on the following evaluation parameters:

Assessment of risk versus benefit to the patients
Innovation vis-à-vis existing therapeutic option
Unmet medical need in the country
Safety/dosage/investigational tests (e.g., pharmacogenetic tests)
Any additional information or study(ies) needed before marketing approval for inclusion in package insert/ summary product characteristic (SmPC) post marketing

See IND-46 for additional information on conducting clinical trials in India. For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

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

Other Considerations

In addition, per the 2019-CTRules and IND-31, the DCGI, with the approval of the Central Government, may waive the requirement to conduct a local trial for a new drug already approved outside India. The waiver will be considered for applications submitted to conduct a trial with a new drug already approved in certain countries if the following conditions are met:

The new drug is approved and marketed in countries to be specified by the DCGI and no major unexpected serious adverse events have been reported, or
The DCGI has already granted permission to conduct a GCT with the new drug that is currently ongoing in India and this new drug has also been approved for marketing in one (1) of the countries to be specified by the DCGI, and
There is no probability or evidence, on the basis of existing knowledge, of any difference in the metabolism of the new drug by the Indian population, or any factor that may affect the pharmacokinetics, pharmacodynamics, and safety and efficacy of the new drug, and
The applicant has committed in writing to conducting a Phase IV clinical trial to establish the new drug’s safety and efficacy per the DCGI-approved formulation

Per the 2019-CTRules, the DCGI plans to issue periodic orders to specify the countries that may be eligible for this waiver. For countries that do not meet the waiver eligibility requirements, the 2019-CTRules states that these applications must be approved by the DCGI within 90 working days from the date of application receipt. Although the 2019-CTRules does not delineate the countries that may be eligible for a waiver, according to IND-19, the United States, the United Kingdom, the European Union, Canada, Australia, and Japan are the countries that will no longer be required to complete local clinical trials for already approved and marketed new drugs. Refer to the Manufacturing & Import section for detailed information on import requirements for new drugs already approved outside of India. See also IND-6 for additional information on local clinical trial waivers under the 2019-CTRules.

Revising New Drug Definition and Waivers of Local Clinical Trial Data

2-3, 7, 10-11, 18, 22, 25, 31-33, 38, and 79

Preface, 4.0, 5.0-5.2, 5.22, 8.2, and Appendix 8.3

4.8 (Table 4.2) and 7.0-7.1

7.11 and Annexures I, II, and III

4, 11.2, and Annexures I and II

1

4-6 and 12

Chapter I (2), Chapter II (3), Chapter III (11), Chapter V (19-26, and 28), Chapter XIII (100-101), First Schedule (3), Second Schedule (1 and Table 1), Third Schedule (1 and Table 4), Fourth Schedule (7), and Eighth Schedule (Forms CT-04, CT-4A, and CT-06)

Regulatory Fees

Last content review/update: June 16, 2023

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

Question 5

Last content review/update: February 2, 2023

Central Drugs Standard Control Organization

As per the 2019-CTRules, IND-43, and IND-42, a sponsor (also known as applicant) is responsible for a paying a fee to the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), to submit a clinical trial application. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

The 2019-CTRules and IND-43 specify that Form CT-04 should be accompanied by one (1) of the following officially mandated fees:

3,00,000 Rupees for Phase I (human) clinical trials
2,00,000 Rupees for Phase II (exploratory) clinical trials
2,00,000 Rupees for Phase III (confirmatory) clinical trials
2,00,000 Rupees for Phase IV clinical trials
50,000 Rupees for reconsideration of application for permission to conduct clinical trial

According to the 2019-CTRules, the sponsor must also submit a fee of 5,000 Rupees per product with an application for permission to manufacture or import the investigational product (IP) to be used in a clinical trial.

In addition, the 2019-CTRules states that no fee is required to be paid along with the clinical trial application if a trial is being conducted by an institution or an organization wholly or partially funded or owned by the Central Government of India or one of India’s state government institute(s).

See also IND-31 for additional information on CDSCO fee requirements.

Payment Instructions

As described in the 2019-CTRules and IND-43, payment must be made electronically via the Bank of Baroda, Kasturba Gandhi Marg, New Delhi-110001, any other Bank of Baroda branch, or any other bank approved by the Ministry of Health and Family Welfare (MOHFW) via the State Bank of India’s SBIePay payment gateway, which is accessed from the SUGAM portal (IND-59). The payment should be credited to: Head of Account, 0210-Medical and Public Health, 04-Public Health, 104-Fees and Fines per the 2019-CTRules, also known as the head of Fees & Fines, according to IND-42.

According to IND-43 and IND-42, once the user validates the payment information in IND-59, the payment request is redirected to the SBIePay payment gateway. When the payment is submitted, the bank payment gateway will confirm that the payment was successful, and the user will be redirected to the online payment status page in IND-59 to view the e-Challan (payment receipt).

IND-43 and IND-42 also specify that the online payment will take two (2) to three (3) days to be credited to the National Portal of India’s Payment & Account Office. Therefore, users are requested to initiate online payments at least three (3) days prior to submitting an application to CDSCO. Refer to IND-43 and IND-42 for detailed fee requirements and online payment instructions via the SUGAM portal.

(Note: Although the fees listed in IND-43 are correct, the SUGAM portal and associated documentation as well as CDSCO’s Pre-Screening Checklist (IND-32) have not yet been aligned with the 2019-CTRules in terms of referencing the new application form (CT-04). However, the ClinRegs team is regularly monitoring the CDSCO website for new developments and will post the most current sources as they become available.)

1 (INDs) and 3 (Global Clinical Trials)

1 and 6

Chapter V (21), Chapter XIII (102), Sixth Schedule, and Eighth Schedule (Form CT-04)

Ethics Committee

Last content review/update: June 16, 2023

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, all proposed or ongoing research involving human participants carried out by, funded by, or otherwise under the auspices of Health Canada (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 known as the HC-PHAC REB. 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, 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. 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), the G-TCPS2 is a policy that 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. For examples of EC SOPs, see CAN-13 for the HC-PHAC REB operational policy.

2 and 3

About the REB and Policies, Guidelines, and Resources

Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11

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)

Part C (Division 5 (C.05.001, C.05.002, C.05.005, C.05.006, and C.05.010))

Last content review/update: February 2, 2023

Overview

As delineated in the 2019-CTRules and IND-31, India has a decentralized process for the ethical review of clinical trial applications, and requires ethics committee (EC) approval for each trial site. Because there is no national EC in the country, ECs are based at either institutions/organizations, or function independently, and must meet the requirements set forth in the 2019-CTRules and the G-ICMR. Prior to initiating and throughout the duration of a trial, every trial site must be overseen by an EC registered with the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO). (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

Ethics Committees for Biomedical and Health Research

Per the 2019-CTRules, CDSCO requires institutions that intend to conduct biomedical and health research to have an EC that reviews and oversees this type of research study. In addition, CDSCO has also established a separate registration and monitoring system for ECs that review biomedical and health research. See the Scope of Review section for additional information on biomedical and research study requirements.

Ethics Committee Composition

Pursuant to the 2019-CTRules and the G-ICMR, an institutional/independent EC should be multidisciplinary and multi-sectorial, representing a mixed gender and age composition. ECs that review clinical trial applications and those that review biomedical and health research share the same composition criteria including affiliations, qualifications, member specific roles and responsibilities, as well as terms of reference and review procedures.

The 2019-CTRules and the G-ICMR state that an EC should appoint from among its members a chairperson (from outside the institution) and a member secretary (generally from inside the institution). The other members should represent a balance of affiliated and non-affiliated medical/non-medical and scientific/non-scientific persons, including the lay public. Per the 2019-CTRules and the G-ICMR, preferably 50% of the members should also be non-affiliated or from outside the institution.

As per the 2019-CTRules and the G-ICMR, the composition should include the following:

Chairperson from outside the institute (Vice Chairperson (optional))
One (1) to two (2) basic medical scientists (preferably one (1) pharmacologist)
One (1) to two (2) clinicians from various institutions
Legal expert(s) or retired judge
One (1) social scientist/representative of non-governmental voluntary agency
One (1) philosopher/ethicist/theologian
One (1) lay person from the community
Member secretary (Alternative Member secretary optional)
One (1) member whose primary area of interest/specialization is non-scientific
At least one (1) member independent of the institution/trial site

Additionally, per the 2019-CTRules, EC members are required to:

Be familiar with key clinical regulatory requirements as delineated in the 2019-CTRules and the G-ICMR that reference both the Declaration of Helsinki (IND-63) and the most recently updated International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (IND-41)
Have post-graduate qualifications and experience in their fields if representing basic medical scientists/clinicians
Represent the specific patient group as much as possible based on the research area requirement

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in the 2019-CTRules and the G-ICMR, EC members should be made aware of their roles and responsibilities. The terms of reference should also include a statement on terms of appointment including duration and conditions; policy for removal/replacement; resignation procedure; meeting frequency; payment of processing fee to EC for review; honorariums to members and invited experts; maintenance of EC documentation and communication records, etc. Each committee should specify these terms in its own standard operating procedures (SOPs) that should be made available to each member.

In addition, per the 2019-CTRules and the G-ICMR, members should have no conflict of interest, and should voluntarily withdraw from the EC while making a decision on an application if a proposal evokes a conflict of interest. The G-ICMR indicates the term of membership is generally two (2) to three (3) years, and may be extended.

In terms of training, the G-ICMR also specifies each member must:

Provide a recent signed Curriculum Vitae (CV) and training certificates on human research protection and good clinical practice (GCP) guidelines, if applicable
Either be trained in human research protection and/or GCP at the time of induction into the EC, or undergo training and submit training certificates within six (6) months of appointment (or as per institutional policy)
Be willing to undergo training or update their skills/knowledge during their tenure as an EC member

Further, if required, the 2019-CTRules and the G-ICMR, state subject experts could also be invited to offer their views, which must be recorded; however, the experts would not have any voting rights. Only members independent of the trial and the trial sponsor (also known as applicant) should vote/provide opinions in study related matters. In addition, all records must be safely maintained after the completion or termination of the study for at least five (5) years from the date of the trial’s completion or termination (both hard and soft copies).

The G-ICMR specifies that all EC members should review all proposals. Members should be given at least one (1) week to review the proposal and related documents, except in the case of expedited reviews. The Member Secretary should screen the proposals for their completeness and categorize them into three (3) types according to risk level: exemption from review, expedited review, or full committee review. An investigator cannot decide that his/her protocol falls in the exempted category without an EC review. Per the 2019-CTRules and the G-ICMR, a minimum of five (5) members is required for the quorum.

For detailed EC procedures and information on other administrative processes, see the 2019-CTRules, the G-ICMR, and IND-5. See also IND-27 and IND-28 for the Indian Council of Medical Research (ICMR)’s research conduct policies.

Sections 1-4

32-33

Sections 1-4

2.1, 2.8, 4.0-4.4, 4.10, Tables 4.1-4.3, Glossary, and Annex 1

Chapters I, III-IV, and V (19-20 and 25); Third Schedule (1 and Table 1); and Eighth Schedule (Forms CT-01 and CT-02)

Scope of Review

Last content review/update: June 16, 2023

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 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 an institutional EC approval for each participating trial site is submitted. The sponsor should use the Clinical Trial Site Information Form (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 EC review and approval of research involving living human participants and human biological materials. Further, ECs must 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.

The G-TCPS2 lays out options, procedures, and considerations for the ethics review of multi-jurisdictional research either entirely within Canada, or in Canada and other countries. An institutional EC may approve alternative review models for research with multiple ECs and/or institutions but remains responsible for the ethics and conduct of research in its jurisdiction or under its auspices regardless of where the research is conducted. See the G-TCPS2 for more information about the various review models for multi-jurisdictional research.

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

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 1-2, 6, 8, and 11

Part C (Division 5 (C.05.001, C.05.005, C.05.006, and C.05.010))

Last content review/update: February 2, 2023

Overview

The primary scope of information assessed by ethics committees (ECs) relates to maintaining and protecting the rights, safety, and well-being of all research participants, especially those in vulnerable populations, in accordance with the requirements set forth in the 2019-CTRules, the G-ICMR, the G-Children, the Declaration of Helsinki (IND-63), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (IND-41). (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these populations).

The 2019-CTRules and the G-ICMR also state that ECs must ensure an independent, timely, and competent review of all ethical aspects of the research protocols. 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. Per the G-Children, ECs providing opinions on studies involving children should also include members with pediatric expertise. The expert(s) may be permanent EC members or invited as subject experts to provide advice and be consulted on an ad-hoc basis.

Role in Clinical Trial Approval Process

As per the 2019-CTRules, the G-ICMR, and IND-31, the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), and a DCGI-registered EC must approve a clinical trial application prior to the sponsor (also known as applicant) initiating the trial, except in the case of non-regulatory academic clinical trials that only require EC approval. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) According to IND-31, the DCGI review and approval process may be conducted in parallel with the EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2019-CTRules, the Hdbk-ClinTrial, and IND-31 specify that an EC must grant a separate approval for each trial site to be used, and the DCGI must be informed of each approval. A trial may only be initiated at each respective site after obtaining an EC approval for that site. The 2019-CTRules and IND-31 further state that if a site does not have an EC, it may obtain approval from another site’s EC provided that it is located within the same city or within a radius of 50 kilometers of the trial site. The DCGI should be notified of the EC’s approval within 15 working days of the approval being granted per the 2019-CTRules. Per the 2019-CTRules and IND-31, the EC of each site should notify the DCGI of its approval and provide a copy within 15 working days of making this decision. Refer to IND-36 for the Indian Council of Medical Research (ICMR)’s EC clinical trials application form.

During a clinical trial, per the 2019-CTRules, an investigator should not implement any deviations from or changes to the trial protocol without agreement by the sponsor and after obtaining the EC’s prior review and documented approval or favorable opinion of the amendment. All protocol amendments should be submitted to the DCGI in writing along with the EC’s approval letter.

The 2019-CTRules further states that the exception to this requirement is when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature. In this case, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should also be notified of administrative or logistical changes or minor amendments in the protocol within 30 days.

As delineated in the 2019-CTRules, ECs also have a continuing responsibility to monitor approved clinical trials and biomedical and health research studies to ensure ethical compliance throughout the study duration.

For all studies, the G-ICMR indicates that ECs must review and approve any protocol amendments, major deviations, or violations at regular intervals.

There is no stated expiration date for an EC approval in the 2019-CTRules or the G-ICMR. However, per the 2019-CTRules, in the event that an EC revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator as well as to the DCGI. For detailed EC review procedures and information on other administrative processes, see the 2019-CTRules, the G-ICMR, IND-5, and IND-27. See also IND-36 for the EC clinical trial application form, and IND-52 for other commonly used EC review forms.

The G-ICMR further states that research during humanitarian emergencies and disasters can be reviewed by an EC through an expedited review and scheduled/unscheduled full committee meetings, and this may be decided by the member secretary on a case-by-case basis depending on the urgency and need. If an expedited review is done, full ethical review should follow as soon as possible. The EC should also closely monitor the conduct and outcome of research. See Section 12.5 of the G-ICMR for additional information on EC review requirements during humanitarian emergencies.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Academic Clinical Trials

As defined by the 2019-CTRules, an academic clinical trial is a clinical trial of a drug already approved for a certain claim and initiated by any investigator, academic or research institution for a new indication or new route of administration, or, new dose or new dosage form, where the results of such a trial are intended to be used only for academic or research purposes and not for seeking DCGI approval or regulatory authority approval in any country for marketing or commercial purpose.

The 2019-CTRules and IND-31 specify that an academic clinical trial does not require DCGI approval as long as the following conditions are met:

The trial is approved by the EC, and
The data generated is not intended for submission to the DCGI

In addition, per the 2019-CTRules and IND-31, the EC should inform the DCGI about the academic trials it has approved and cases where there could be an overlap between the clinical trial for academic and regulatory purposes. If the DCGI does not comment to the EC within 30 days from receiving EC notification, it should be presumed that DCGI permission is not required. See also IND-6 for additional information on academic trial approval requirements.

IND-25 further explains that a drug import license is not required for EC-approved academic trials that will be using a permitted drug formulation with a new indication, a new route of administration, a new dose, or a new dosage form. See the Manufacturing & Import section for detailed information.

Biomedical and Health Research

According to the 2019-CTRules and the G-ICMR, biomedical and health research is defined as studies that include basic research, applied and operational research, or clinical research designed primarily to increase scientific knowledge about diseases and conditions (physical or socio-behavioral); their detection and cause; and evolving strategies for health promotion, prevention, or the amelioration of disease and rehabilitation.

As discussed in Notice15Sept19 and Chapter IV of the 2019-CTRules, any institution or organization that intends to conduct biomedical and health research involving human participants is required to have an EC to review and oversee the conduct of such research before the study is initiated and throughout its duration. See also IND-28 for ICMR’s biomedical and health research conduct policies, and IND-6 for additional information on the regulation of biomedical and health research under the 2019-CTRules.

The EC must also be registered with the designated authority within the Ministry of Health and Family Welfare (MOHFW)’s Department of Health Research (DHR). Refer to the Oversight of Ethics Committees section for detailed registration requirements.

Multicenter Research

As delineated in the G-ICMR, in a multicenter research study, all of the participating study sites are required to obtain approval from their respective ECs. Each EC may conduct a separate review, or the ECs may decide to designate a main EC, with the others choosing to accept its decision. The study sites also typically follow a common protocol to avoid duplication of effort, wastage of time, and issues arising with communication between committees.

Per the G-ICMR, in the event that sites choose to have separate EC reviews, the following requirements must be met:

The participating site ECs/Secretariats should establish communication with one another
If any EC does not grant approval for a study at a site, the reasons must be shared with other ECs and should be considered
The EC can suggest site-specific protocols and informed consent modifications as per local needs

A separate review may be requested for studies with a higher degree of risk, clinical trials, or intervention studies where conduct may vary depending on the site, or, for any other reason that requires closer review and attention. See the G-ICMR for additional participating site requirements when a primary EC is selected for common EC review.

Per the G-ICMR, when the multicenter research study designates one (1) main EC, the nominated EC members that represent the participating sites may attend the meeting of the elected EC. The designated EC should also be located in India and be registered with the relevant authority (either the DCGI or the DHR depending on the type of study). In addition, the decision to conduct a common review is only applicable for ECs in India. In the case of international collaboration for research and approval by a foreign institution, the local participating study sites would be required to obtain approval from a local EC. Refer to the G-ICMR for detailed information on multicenter studies that use the common review practice and involve international collaborations.

The G-ICMR further notes that the local site requirements (e.g., informed consent, research implementation and its monitoring) may be performed by the local EC, which would require good communication and coordination between the researchers and the EC secretariats representing the participating sites.

1-4

Regulations on Biomedical and Health Research (BHR) and Academic Trials

2, 11, and 31-35

Introduction and Sections 1-4, and 6

1.27 and 3.1

Preface, 4.0, 5.0-5.2, 8.2, and 8.3

3.1

1.0-1.1, 2.1, 2.3, 2.8-2.9, 4.0, 4.2, 4.7-4.8, 4.11, Tables 4.1-4.3, 12.5, Glossary, and Annex 1

7.11 and Annexures I, II, and III

4, 11.2, and Annexures I and II

Chapter I, Chapter III (7 and 11), Chapter IV (15-17), Chapter V (19-20, 25, and 28), and Third Schedule (1, 3, and Table 4)

Ethics Committee Fees

Last content review/update: June 16, 2023

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.

REB Review Fees

Last content review/update: February 2, 2023

As indicated in the G-ICMR, ethics committees (ECs) may charge a reasonable fee to cover the expenses related to optimal functioning to conduct reviews. EC members may also be given reasonable compensation for their time attending EC meetings, and every institution should allocate adequate funds to ensure the smooth functioning of the EC.

4.14

Oversight of Ethics Committees

Last content review/update: June 16, 2023

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

Last content review/update: February 2, 2023

Overview

In accordance with the 2019-CTRules and IND-31, all ethics committees (ECs) that review drug clinical trials are required to register with the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), prior to reviewing and approving a clinical trial protocol. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) As delineated in Notice15Sept19 and Chapter IV of the 2019-CTRules, all ECs that review biomedical and health research studies are required to register with the designated authority within the Ministry of Health and Family Welfare (MOHFW)’s Department of Health Research (DHR). According to IND-50, the DHR’s Office for Ethics Committee Registration has been designated as the entity responsible for coordinating and monitoring registrations for ECs overseeing biomedical and health research in India. This office will receive applications for registration of ECs and will review and make decisions on EC registrations/re-registrations.

See also IND-69 for an application submission checklist to re-register ECs. Refer to IND-49 for a list of registered ECs, and IND-48 for a list of re-registered ECs.

Registration, Auditing, and Accreditation

Registration Provisions for Clinical Trial Ethics Committees

As specified in the 2019-CTRules and Notice1Aug18, ECs that intend to review clinical trial research protocols must submit Form CT-01 via the SUGAM portal (IND-59) to register with the DCGI. The DCGI, in turn, will review the application within 45 working days from the date of receipt and, if satisfied with the information provided, grant the EC's registration request via Form CT-02. Per 2022-CTRules-3rdAmdt, provided that no communication has been received from the DCGI within the stated period of 45 working days, the EC registration will be deemed granted by the DCGI, and such registration will be regarded as legally valid for all purposes and the applicant will be authorized to initiate a clinical trial in accordance with these rules. 2022-CTRules-3rdAmdt further states that once the EC has obtained provisional approval from the DCGI per the 2019-CTRules, the committee must also notify CDSCO via Form CT-02A, which will become part of the official record known as the guaranteed registration of the DCGI.

Per the 2019-CTRules and IND-53, the EC registration will remain valid for a period of five (5) years from the date of issue, unless suspended or cancelled sooner. The EC may apply for registration renewal via the SUGAM portal using Form CT-01 and should include all additional required documentation 90 days prior to the registration’s expiration date. The registration will remain in force until the DCGI passes a new registration order as long as the application is received within the specified 90-day deadline. Following the DCGI’s review of the application and inspection report, if any, and provided that there are no changes to the documentation included in the original application, the EC’s request for registration renewal will be granted within 45 working days from the date of application receipt. See also IND-42 and IND-43 for detailed fee requirements and online payment instructions via the SUGAM portal.

The 2019-CTRules also states that if the EC fails to comply with any of the registration conditions, the DCGI may, after giving the EC an opportunity to show cause as to why such an order should not be passed, prepare an order in writing to suspend or cancel the EC registration for such period as deemed necessary. The suspended or cancelled EC can appeal to the DCGI within the period specified in the show cause notice, and, after consideration, the DCGI may respond by taking one (1) or more of the following actions:

Withdraw the notice
Issue a warning to the EC describing the deficiency or defect observed during an inspection
Reject the results of the clinical trial
Suspend for a specified period or cancel the registration, or
Debar its members to oversee any future trial for a specified period

The aggrieved EC may file an appeal to the Government of India (Central Government) within 60 working days. The Central Government may subsequently pass an order in response to the appeal within 60 working days from the date of the appeal filing.

The EC must also allow CDSCO officials to enter the committee premises to inspect any records, data, documents, or other materials related to a clinical trial. The EC must provide adequate replies to any queries raised by the inspecting authority in relation to the conduct of the trial as noted in the 2019-CTRules.

Registration Provisions for Biomedical and Health Research Ethics Committees

As explained in Notice15Sept19 and IND-51, ECs planning to review biomedical and health research studies are initially required to register on the DHR’s National Ethics Committee Registry for Biomedical and Health Research (NECRBHR) website (IND-51). The NECRBHR facilitates the receipt and processing of application submissions and assists the DHR’s Office of Ethics Committee Registration. An authorized signatory/responsible person must complete the EC Applicant Registration Form (IND-38) and submit it online on the NECRBHR website (IND-51). Once the NECRBHR verifies the application and approves the account registration, the applicant will receive an email with login instructions to submit an application electronically via the DHR’s NAITIK portal (IND-54). See IND-66 for a checklist of NECRBHR registration requirements.

Per the 2019-CTRules, the EC must submit an application to the NECRBHR using Form CT-01 along with the required information and documentation specified in Table 1 of the Third Schedule of the 2019-CTRules. Upon receipt of the application, the DHR’s Office of Ethics Committee Registration (designated authority) must grant provisional registration to the EC for a period of two (2) years. Final registration will be granted to the EC on Form CT-03 when the DHR has completed its review of the application and the associated documentation. The final registration will remain valid for a period of five (5) years from the date of its issue, unless suspended or cancelled sooner.

The EC may also submit an application to request registration renewal using Form CT-01 along with the specified documentation at least 90 days prior to the final registration’s expiration date. The final registration will remain in force until the DHR completes its review of the renewal application provided that the following conditions are met:

The DHR does not require the EC to provide a new set of documents
There have been no changes in the submitted documents since the final registration was granted, and
The EC submits a certificate to the DHR validating that the documents have not changed

Following a review of the registration renewal application and further inquiry to confirm there have been no documentation changes, the DHR will renew the EC’s registration on Form CT-03 within 45 working days from the date of application receipt. The renewed registration will remain valid for five (5) years from the date of its issue, unless suspended or cancelled sooner.

The 2019-CTRules further states that if the EC fails to comply with any of the registration conditions, the DHR may, after giving the EC an opportunity to show cause as to why such an order should not be passed, prepare an order in writing to suspend or cancel the EC registration for such period as deemed appropriate. The suspended or cancelled EC can appeal to the DHR, and after consideration, the DHR may respond by taking one (1) or more of the following actions:

Issue a warning to the EC describing the deficiency or defect observed, which may adversely affect the rights or well-being of the study participants
Suspend the EC for a specified period or cancel the registration, or
Debar its members from overseeing any future biomedical health research for a specified period

The aggrieved EC may file an appeal to the Government of India (Central Government) within 45 working days. In response to the appeal, as deemed necessary, and after giving the EC an opportunity to be heard, the Central Government may subsequently pass an order considered appropriate to the case.

(Note: The registration provisions for biomedical and health research ECs in Notice15Sept19 and IND-51 have not yet been aligned with the 2019-CTRules in terms of explaining the application submission process. The 2019-CTRules does not specify that the application submission process is electronic as is stated in Notice15Sept19 and IND-51. Further, only Notice15Sept19 and IND-51 specify that the DHR’s Office of Ethics Committee Registration is the designated authority. However, the ClinRegs team is regularly monitoring the CDSCO website for new developments and will post the most current sources as they become available.)

Additional Provisions for Clinical Trial and Biomedical and Health Research Ethics Committees

In addition to requiring all ECs to register with the relevant regulatory authority (the DCGI or the DHR), the G-ICMR specifies that ECs should be encouraged to seek recognition, certification, and accreditation from established national and international bodies (e.g., the SIDCER-FERCAP Foundation, the Association for the Accreditation of Human Research Protection Programs (AAHRPP), CDSCO, and the Quality Council of India through National Accreditation Board for Hospitals and Healthcare Providers (NABH), etc.). Although voluntary, the G-ICMR states that these certifications and accreditations should be continually updated to help with quality assurance and quality improvement and ensure that ECs comply with best practices to protect research participants.

32-33

1 and 6

Registration of Ethics Committees reviewing Biomedical & Health Research

4.1 and 4.15

2-3, 12, and Form CT-02A

Chapter III (6, 8-11, and 14), Chapter IV, and Chapter V (19-20 and 25), Third Schedule (Table 1), and Eighth Schedule (Forms CT-01, CT-02, and CT-03)

Submission Process

Last content review/update: June 16, 2023

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 an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form (CAN-6)) for each participating trial site is submitted. The HCNotice-CTSIForm indicates that the 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. The G-Canada-CTD provides detailed CTD format/structure requirements.

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." Per ElecSubms, applicants must submit CTAs electronically in either eCTD format or non-eCTD format. According to the G-MDSA, HC does not accept paper copies of CTAs, CTA amendments, and CTA notifications.

The G-MDSA and the G-CanadaCTApps indicate that sponsors may request a pre-submission/application meeting with the appropriate Directorate within the 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.

eCTD Electronic Submission

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.

Non-eCTD Electronic Submission

For non-eCTD electronic submissions, Non-eCTDformat indicates that HC requires both PDF and MS-Word formats for the CTA (CAN-4). The PDF documents must be generated from electronic sources (not scanned material), except when access to an electronic source document is unavailable or where a signature is required. It is important that PDF files be properly bookmarked and hyperlinked. Documents that legally require signatures may be signed with an electronic signature, or the signature page can be printed, signed, scanned, and saved as a PDF file. The cover letter does not require a signature, but should include a printed name, phone number, and email address. All regulatory submissions should be validated prior to transmitting to HC. For validation rules, see the Rules-Non-eCTD. The ElecSubms contains a zip file of the folder structure for clinical trial non-eCTD submissions.

Per the Non-eCTDformat, CTA submissions to the appropriate Directorate within HC’s HPFB must be in one (1) of these accepted media formats:

Compact Disc-Recordable (CD-R) conforming to the Joliet specification
Universal Serial Bus (USB) 2.0 or 3.0 drive
Digital Versatile Disc (DVD-RAM and DVD+R/-R) in Universal Disk Format (UDF) standard

All media should be labelled and contain the following information:

Sponsor Name
Brand Name
Dossier ID (if known)

Subsequent to burning the CD/DVD or transferring data to a drive, applicants should ensure that all files can be opened, files are not corrupted, and that "Thumb.db" files are removed.

As per the Non-eCTDformat, 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 Canada
5th Floor, Holland Cross, Tower B
1600 Scott Street, Address Locator: 3105A
Ottawa, Ontario, Canada
K1A 0K9
General Inquiries E-mail: oct.enquiries-requetes.bec@hc-sc.gc.ca

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
Ground Floor, Health Canada Building 6
100 Eglantine Driveway
Address Locator: 0601C
Ottawa, Ontario, Canada
K1A 0K9
General Enquiries E-mail: brdd.ora@hc-sc.gc.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.

Per the Non-eCTDformat, if an applicant submits a non-eCTD CTA via email, they should meet the following requirements:

The maximum email size accepted by the corporate mail server is 20 megabytes. If the clinical trial submission is larger than 20 megabytes, the submission may be split and sent as separate emails (e.g., an email for Module 1, and another email for Module 2/3). The subject line of the emails should clearly link to each other (e.g., "Email 1 of 2" in the relevant subject line)
A duplicate copy must not be provided by mail
The submission should be organized in folders and the body of the email should only contain the zipped regulatory submission
Zipped files and documents contained in the email should not be password protected

The Non-eCTDformat provides additional information on emailing other clinical trial submissions, including responses to a clarification request, responses to a no objection letter, notifications, and development safety update reports.

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.

Guidance documents, notices, and supporting documents

1.2, 2.2, 2.3, and 2.7

7.1, 8.1, and 8.2

5.2, 5.4, and 5.5

2-5, and Appendix D

1.2, 3, and Appendix B

Part C (Division 5 (C.05.002, C.05.004, C.05.005))

Last content review/update: February 2, 2023

Overview

In accordance with the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, the sponsor (also known as the applicant) is required to submit a clinical trial application to the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), to obtain authorization to conduct a clinical trial in India. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) The investigator must also obtain ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. According to IND-31, the DCGI review and approval process may be conducted in parallel with the EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.) Refer to IND-42 for instructions on uploading forms and related documentation to the SUGAM portal (IND-59).

For specific guidelines regarding gene therapy and stem cell therapy clinical trial submissions, see G-GeneThrpy and G-StemCellRes.

Regulatory Submission

As indicated in the Notice15Jan18, all clinical trial application submissions must be submitted electronically via CDSCO’s SUGAM portal (IND-59).

The DCA-DCR delineates that English should be used for specific documents included in the clinical trial application submission. For the informed consent form and patient information sheet, English and/or the vernacular language of the participant(s) should be used. English should also be used for the package inserts.

Ethics Review Submission

As indicated in the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, India requires all clinical trials of drugs involving human participants to be reviewed by a DCGI-registered EC. Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements. The G-ICMR also specifies that investigators should submit research proposals as soft or hard copies to the EC Secretariat for review in the prescribed format and required documents as per EC standard operating procedures (SOPs).

31-33

1 and 4

5.0-5.2 and Appendix 8.3

4.0-4.2, 4.8, and 4.10

7.11 and Annexures I, II, and III

4, 11.2, and Annexures I and II

Appendix VIII and Schedule D(II)

Chapter I (2), Chapter II (3), Chapter V (19-22, and 25), Second Schedule (1), Third Schedule (1 and Tables 3, 6, and 7), and Eighth Schedule (Forms CT-04, CT-4A, and CT-06)

Submission Content

Last content review/update: June 16, 2023

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-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

Refer to the CanadaFDR, 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.

Apply for Ethics Review

3.1.2, 6, and 7

2.3 and 2.7

2-5, and Appendix D

I, S Drug Substance, and P Drug Product

Chapter 11 (Article 11.6)

Part C (Division 5 (C.05.001, C.05.004, and C.05.005))

Last content review/update: February 2, 2023

Regulatory Authority Requirements

As per the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35, documentation must be submitted to the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), as part of the approval process for investigational new drugs (INDs) will depend upon the type of application, phase of the study, stage in drug development process, and/or objective of the study. Information that may be required is included in the lists below (Note: The regulatory sources provide overlapping and unique elements so each of the items listed above will not necessarily be in each source):

Form CT-04 (the clinical trial application form including sponsor (also known as applicant) name; sponsor nature/constitution and contact information; clinical trials site contact information and details; contact information for person responsible for compensation payment, if any; correspondence address; new drug/investigational new drug name(s) and details (i.e., therapeutic class, dosage form, composition, and indications); clinical trial phase; protocol number with date; and ethics committee (EC) and investigator names)
Treasury Challan receipt demonstrating payment of corresponding fee or transaction ID
Chemical and pharmaceutical information
Animal pharmacology data
Animal toxicology data
Human clinical pharmacology data
Active ingredient information (for INDs and global clinical trials (GCTs))
Formulation data (for INDs and GCTs)
Therapeutic class (for INDs and GCTs)
Regulatory status in India and in other countries
Proposed study status in other participating countries and any approvals, withdrawals, discontinuation of approval, etc. (for GCTs)
Affidavit stating study has not been discontinued in any country (for GCTs)
Prescribing information
Testing protocol(s) for quality control testing
Clinical study protocol
Dosage form
Justification and schematic diagram/flow chart proposed study and design (for INDs and GCTs)
Number of patients globally (for GCTs) and number of patients to be enrolled from India (for INDs and GCTs)
Details of all sites selected and assessment for suitability of sites and investigators (with contact details)
EC registration status of the selected sites
Relevance of study, investigational drug, or any specific study aspects to the health care needs of India
Innovation vis-à-vis existing therapeutic options
Unmet medical need in the country (as applicable)
Any India-specific safety/dosage concerns/investigational tests to be done
Clinical study reports should be submitted per the International Conference on Harmonisation (ICH) Common Technical Document (CTD) (IND-68)
Protocol safety measures per toxicological studies; early clinical studies, approved product insert for marketed product, and published literature
Investigator’s Brochure (IB)
Investigational Medicinal Products Dossier (IMPD) (for (GCTs))
Affidavit stating the IB information is correct and based on facts (for GCTs)
Source of bulk drugs (for INDs)
Treasury Challan with Form CT-16 (import license application) (for GCTs)
Sponsor authorization letter (for GCTs)
Details of biological specimens to be exported and the online application for export no objection certificate (NOC) for biological samples on the SUGAM portal (IND-59) (for GCTs) (See IND-1 for the application form to request a NOC to export biological samples) (Refer to the Specimens topic for more information on specimen import/export)
Case Report Form (CRF)
Informed consent form (ICF) and patient information sheet (See Required Elements section for additional information)
Investigator(s) undertaking
EC approvals (if available)
Clinical study report(s)
Investigator list in India and site address

See the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35 for detailed DCGI application submission requirements. See also IND-22 for details on the SUGAM portal approval process for GCTs and IND-31 for clinical trial FAQs. (Note: The Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Refer to the 2019-CTRules and IND-31 to obtain detailed submission requirements for applications to conduct a clinical trial using an already approved new drug with a new indication, a new dosage form/new route of administration, a modified release dosage form, or a new drug with an additional strength.

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, per the G-ICMR, the requirements listed below are basically consistent and shared by all of the Indian ECs:

Cover letter to the Member Secretary
Type of review requested
Application form for initial review (IND-39)
Informed consent document (in English and the local language(s)) including translation and back translation certificates, if applicable
Case record form/questionnaire
Recruitment procedures (e.g., advertisement, notices) if applicable
Patient instruction card, diary, etc., if applicable
IB (as applicable for drugs, biological, or device trials)
Details of funding agency/sponsor and fund allocation, if applicable
Investigators’ Curriculum Vitaes (CVs)
Conflict of interest statement, if applicable
Good Clinical Practice (GCP) training certificate for investigators (preferably within last five (5) years)
Any other research ethics/other training evidence, if applicable as per EC standard operating procedures (SOPs)
List of ongoing research studies undertaken by the principal investigator, if applicable
Investigator’s undertaking statement with all participating investigator signatures
Regulatory permissions (as applicable)
Relevant administrative approvals (such as Health Ministry’s Screening Committee (HMSC) approval for international trials)
Institutional Committee for Stem Cell Research (IC-SCR) Registration (IND-72), if applicable
Memorandum of Understanding (MoU) in case of studies involving collaboration with other institutions, if applicable
Clinical trial agreement between the sponsors, investigator, and the head of the institution(s), if applicable
Clinical trial registration documentation (preferable)
Insurance policy (it is preferable to have the policy as well as the insurance certificate) for study participants indicating conditions of coverage, date of commencement and date of expiry of coverage of risk (if applicable)
Indemnity policy, clearly indicating the conditions of coverage, commencement date, and expiry date of risk coverage (if applicable)
Any additional document(s), as required by EC (such as other EC clearances for multicentric studies)
Protocol

Furthermore, the ICMR has prepared a generic application for initial review (IND-39) that may be used by the EC. The form is also included in the bulleted list above.

Clinical Protocol

As delineated in the 2019-CTRules, the Hdbk-ClinTrial, and the G-ICMR, the clinical study protocol should include the following elements:

Title page
Table of contents
Brief summary (G-ICMR)
Study rationale
Study objective
Study design and methodology
Study population
Justification of inclusion/exclusion of vulnerable populations (G-ICMR)
Participant eligibility and recruitment procedures
Study assessments
Study conduct stating the types of activities that would be included (e.g., medical history, type of physical examination, etc.)
Study treatment
Ethical consideration
Study monitoring and supervision
Investigational product management (See Investigational Products topic for detailed coverage of this subject)
Data analysis
Undertaking by the Investigator statement
Appendices

The G-ICMR also mentions the following requirements:

Study duration
Justification for placebo, benefit-risk assessment, plans to withdraw; if standard therapies are to be withheld, justification for the same
Informed consent procedure and sample of the patient/participant information sheet and informed consent forms including audiovisual recording, if applicable, and informed consent for stored samples
Plan to maintain the privacy and confidentiality of the study participants
Adverse events/adverse drug reactions
For research involving more than minimal risk, an account of management of risk or injury
Proposed compensation, reimbursement of incidental expenses and management of research related injury/illness during and after research period
Provision of ancillary care for unrelated illness during the duration of research
Account of storage and maintenance of all data collected during the trial
Plans for publication of results while maintaining confidentiality of participants’ personal information/identity

For detailed information on these elements, see the 2019-CTRules, the Hdbk-ClinTrial, and the G-ICMR.

Chapter V (19-22), Second Schedule (1, 3, and Tables 1-4), Third Schedule (1 and Tables 1-4, and 6-7), Fourth Schedule (Table 3), Sixth Schedule, and Eighth Schedule (Forms CT-04, CT-4A, CT-06, and CT-16)

4.0-4.1, 4.8, and 4.10

Preface, 3, 5.0, 5.1, 5.2, and Appendix 8.3 and 8.4

10-11 and 31-33

1 (INDs) and 3 (Global Clinical Trials)

Timeline of Review

Last content review/update: June 16, 2023

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 an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form) for each participating trial site is submitted. 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.

Apply for Ethics Review

3.1.2

2.1, 2.3.3, 2.5, and 2.7

11.1, 12.1, and 13.3-13.4

5.5 and 5.6

Chapter 2 (Articles 2.8 and 2.9) and Chapter 6 (Article 6.13)

Part C (Division 5 (C.05.005 and C.05.006))

Last content review/update: February 2, 2023

Overview

Based on the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, the review and approval of a clinical trial application by the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), is dependent upon obtaining ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) According to IND-31, the DCGI review and approval process may be conducted at the same time as the EC review for each clinical trial site, except in the case of non-regulatory academic clinical trials that only require EC approval. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Regulatory Authority Approval

As specified in the 2019-CTRules and IND-31, upon receipt of a clinical trial application , the DCGI has 90 calendar days to evaluate the application for a new drug or an investigational new drug; 90 calendar days to evaluate a new drug already approved outside India; and 30 days to evaluate a drug discovered, researched, and manufactured in India. Per the Hdbk-ClinTrial, upon receipt of an application, a CDSCO official conducts the initial administrative review. If the application is deemed complete, within four (4) weeks following receipt, the official forwards the application along with a summary of his/her evaluation and a statement referring the proposal to a Subject Expert Committee (SEC) for further technical review.

The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with the specialization in relevant fields to evaluate scientific and technical drug-related issues. The committee/group may submit its recommendations within 60 days from the date of the request. See the Scope of Assessment section for more information on SEC composition and review processes.

Once the SEC has completed its review, the Hdbk-ClinTrial indicates that the committee sends its comments via email to CDSCO. CDSCO will then compile any written SEC comments requiring sponsor (also known as applicant) clarification or modification and send this feedback to the sponsor within one (1) week of receipt. The applicant must submit a written reply to CDSCO within four (4) weeks of receiving the comments, which will, in turn, be sent to the SEC for review.

Following receipt of the sponsor’s response, the DCGI (CDSCO) will issue a final decision by official communication (permission, rejection, or resubmission) to the Technical or Apex Committee within 15 days. In the case of a sponsor’s request for reconsideration, CDSCO will review the resubmitted application and send it to the SEC again or to the Technical Committee per the sponsor’s request. Following the SEC’s review, the DCGI (CDSCO) will send a final decision to the Technical or Apex Committee within 15 days. If CDSCO rejects the reconsideration request, the agency will send a letter to the sponsor to communicate this decision. Refer to the Hdbk-ClinTrial for additional timeline information.

See also IND-22 for details on the SUGAM portal (IND-59) approval process for global clinical trials, and IND-46 for additional information on conducting clinical trials in India.

Per the 2022-CTRules-3rdAmdt, which amends the 2019-CTRules, provided that no communication has been received from the DCGI within the stated period of 90 working days, permission to conduct all new drug or investigational new drug clinical trials as well as clinical trials for new drugs already approved outside India will be deemed granted by the DCGI. This permission will be regarded as legally valid for all purposes and the applicant will be authorized to initiate a clinical trial in accordance with these rules. Similarly, per the 2019-CTRules and IND-31, if the DCGI does not respond within 30 days to applications for drugs developed in India, the sponsor may conclude that permission to conduct the trial has been granted. Refer to the Scope of Assessment section for information on obtaining a waiver for an already approved drug. See also the Manufacturing & Import section for detailed information on import requirements for new drugs already approved outside of India.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

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

Ethics Committee Approval

As per IND-9, the EC review and approval process, which occurs at the same time as the DCGI review and approval, generally takes from four (4) to six (6) weeks. Many study sites also have scientific review committees (SRCs) review the scientific justification of the study. Once the SRC approves the study, it is submitted to the EC for its review and approval.

The G-ICMR indicates that EC members should be given enough time (at least one (1) week) to review the proposal and related documents, except in the case of expedited review. While all EC members should review all submitted proposals, each EC may adopt different procedures for protocol review per their standard operating procedures.

India

10-11, 18-19, 22, 25, 31-33, 38, and 79

5.0-5.2 and Appendix 8.3

4.1-4.2, 4.8, and 4.10

7.11 and Annexures I, II, and III

4, 11.2, and Annexures I and II

4-6 and 12

Chapter I (2), Chapter II (3), Chapter V (19-25 and 28), Chapter XIII (100-101), First Schedule (3), Second Schedule (1 and Table 1), Third Schedule (1 and Table 6), and Eighth Schedule (Forms CT-04, CT-4A, and CT-06)

Initiation, Agreements & Registration

Last content review/update: June 16, 2023

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 (CTSI) Form (CAN-6), the trial commencement date 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, a copy of HC’s clinical trial authorization (i.e., the NOL) must be included 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

1.2 and 2.7

5.6

Chapter 11 (Articles 11.10-11.11)

Part C (Division 5 (C.05.006))

Last content review/update: February 2, 2023

Overview

As set forth in the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, a clinical trial can only commence in India after the sponsor (also known as applicant) receives permission from the Drugs Controller General of India (DCGI) and approval from the respective ethics committees (ECs). The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations. According to the 2019-CTRules and IND-31, non-regulatory clinical trials intended for academic/research purposes only require institutional EC approval. (See the Scope of Review section for additional details). There is no waiting period required following the sponsor’s receipt of these approvals. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2022-CTRules-3rdAmdt, which amends the 2019-CTRules, further indicates that once the sponsor obtains approval from the DCGI for a new drug, an investigational new drug, or a new drug already approved outside India, the sponsor must notify CDSCO via Form CT-06A prior to initiating the clinical trial. The DCGI will then record the information provided on the form and it will become part of the official record known as the automatic approval of the DCGI.

In addition, per the 2019-CTRules and IND-31, the sponsor is required to obtain approval from the DCGI to manufacture or import investigational products (IPs) and to obtain an import license for the shipment of IPs to be used in the trial. (See the Manufacturing & Import section for additional information.)

As explained in the 2019-CTRules and IND-31, the EC should notify the DCGI about the academic trials it has approved and about cases where there could be an overlap between a clinical trial for academic and regulatory purposes. If the DCGI does not provide comments to the EC within 30 days from receiving EC notification, then it should be presumed that DCGI permission is not required.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Clinical Trial Agreement

According to the 2019-CTRules, the sponsor must have an agreement with the investigator, which is to be provided to the EC. Furthermore, the investigator must sign an undertaking to conduct the trial in accordance with the protocol, good clinical practice guidelines, and all applicable requirements, among other things. For more details, see Table 4 (Third Schedule) in the 2019-CTRules.

Clinical Trial Registration

Per the 2019-CTRules, the G-ICMR, and IND-31, it is mandatory for all sponsors to register their clinical trials, including academic trials, with the Indian Council of Medical Research (ICMR)’s Clinical Trials Registry - India (CTRI) (IND-57) before initiating a study. Refer to the Scope of Review and Submission Process sections for further information on academic trials.

According to IND-56, registrants are advised to factor in a minimum of 10-15 working days for trial review, verification, and validation and the submission must indicate “Not Yet Recruiting” for the trial’s status. A REF number is issued to those registrants who have successfully submitted a trial to CTRI.

In addition, per IND-10, the ICMR has agreed to adopt the United Nation’s recommendations to register and publicly disclose results from all funded or supported clinical trials. The ICMR, along with other participating healthcare bodies, plans to develop and implement policies that require all trials they fund, co-fund, sponsor, or support to be registered in a publicly available registry. All study results will also be released within specified timeframes on the registry or through scientific journal publications. (Note: The CTRI (IND-57) has not been updated as of September 30, 2022.)

See the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35 for detailed DCGI application submission requirements.

10-11, 23-24, 32-33, 37, 64-67, and 71-75

1 (INDs), 2 (New Drugs), 5 (Test License), and 7 (New Drug Formulation)

5.0, 5.1, 5.2, and Appendix 8.3

4.1, 4.2, 4.8, and 4.10

7.11 and Annexures I, II, and III

4, 11.2, and Annexures I and II

5-6, 12, and Form CT-06A

Chapter I (2), Chapter II (3), Chapter V (19-22, 25, and 28), Chapter VIII (52), Chapter IX (67), First Schedule (3), Second Schedule (1 and Table 4), Third Schedule (1, Table 1 and Table 4), Sixth Schedule, and Eighth Schedule (Forms CT-04, CT-4A, CT-06, CT-10, and CT-16)

Safety Reporting

Last content review/update: June 16, 2023

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 ADRs 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 when requested by HC. A DSUR may be submitted voluntarily to HC when important new safety information on a drug needs to be conveyed by a clinical trial sponsor. In these cases, a rationale/justification for the filing of the DSUR should be 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.

Additionally, the G-DSUR indicates that HC recommends that DSURs in electronic Common Technical Document (eCTD) format be submitted via the Common Electronic Submission Gateway (CESG). For information on eCTD format, refer to the ElecSubms. For technical questions on eCTD filings, contact ereview@hc-sc.gc.ca as instructed in the G-DSUR. Per the Non-eCTDformat, DSURs in "non-eCTD electronic-only" format should be sent via email to brdd.cta-dec.dmbr@hc-sc.gc.ca for biologic and radiopharmaceutical drugs and pdd-pv-dmp@hc-sc.gc.ca for pharmaceutical drugs. The subject line of the email should include the statement: "DSUR – drug name", and the zipped file should be named: "DSUR-drugname".

Attachment 1

1.1, 1.2, 1.50, 1.60, and 4.11

Notice, 1.2, and 2.4

2.1 and 2.8

5.14

3.4.3

Chapter 11 (Article 11.8)

Part C (Division 5 (C.05.001 and C.05.014))

Last content review/update: February 2, 2023

Safety Reporting Definitions

In accordance with the 2019-CTRules, the G-ICMR, and IND-42, the following definitions provide a basis for a common understanding of India’s safety reporting requirements:

Adverse Event (AE) – Any untoward medical occurrence (including a symptom/disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a patient or a human participant not necessarily related to the treatment
Adverse Drug Reaction (ADR) – a noxious and unintended response at doses normally used or tested in humans (in cases of approved pharmaceutical products); a noxious and unintended response at any dose(s) (in cases of new unregistered pharmaceutical products); an untoward medical occurrence seemingly caused by overdosing, abuse/dependence and interactions with other medicinal products (in clinical trials)
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – an AE or ADR that is associated with death, in-patient hospitalization (in case the study was being conducted on outpatients), prolongation of hospitalization (in case the study was being conducted on in-patients), persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening. Per IND-42, Important Medical Events may be considered SAEs when they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one (1) of the outcomes listed in this definition
Unexpected Adverse Drug Reaction – an ADR, the nature or severity of which is not described in the informed consent/information sheet or the applicable product information, such as an investigator’s brochure (IB) for the unapproved investigational product (IP) or package insert/summary of product characteristics for an approved product (G-ICMR)

Safety Reporting Requirements

Per the 2019-CTRules, the sponsor (also known as applicant) and the investigator must forward any SAE/SADR report, after due analysis, within 14 days of the occurrence to the Drugs Controller General of India (DCGI), the ethics committee (EC) Chairman, and the head of the institution where the trial is being conducted. (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

In the event of an SAE/SADR resulting in death, per the 2019-CTRules, the sponsor or the representative and the investigator must forward the SAE/SADR reports to the DCGI within 14 days of knowledge of this occurrence. The 2019-CTRules and IND-42 also indicate that the EC is also required to forward its report along with its opinion on financial compensation, if any, to be paid by the sponsor or the representative, to the DCGI within 30 days of the incident.

See Table 5 of the 2019-CTRules for details on the data elements required for reporting SAEs/SADRs that occur during a clinical trial.

See the Insurance & Compensation section for additional information on sponsor compensation requirements.

Investigator Responsibilities

As indicated in the 2019-CTRules, the G-ICMR, and IND-42, the investigator must report all SAEs/SADRs to the DCGI, the sponsor or the representative, and the EC, within 24 hours of occurrence. Per the 2019-CTRules, in the event that the investigator fails to report any SAE/SADR within the stipulated period, he/she is required to provide reasons for the delay to the DCGI along with the SAE/SADR report for the DCGI’s approval.

In addition, per the G-ICMR, the investigator must submit a report to the DCGI explaining how the SAE/SADR was related to the research within 14 days. According to the 2019-CTRules, the investigator must also promptly report to the EC all changes in the clinical trial activities and all unanticipated problems involving risks to human research participants or others.

Form Completion & Delivery Requirements

As per Notice25Feb21, the investigator, the sponsor or the representative, and the EC must report all SAEs electronically via the SUGAM portal (IND-59). However, follow-up reports pertaining to SAE reports submitted prior to March 14, 2021, will continue to be accepted in paper form. Refer to IND-59 for the SUGAM user manual and video tutorials. See also IND-42 for instructions on how to submit SAE reports (referred to as Due Analysis Reports) via the SUGAM portal (IND-59).

The G-ICMR further states that the investigator may report SAEs/SADRs to the EC through email or fax communication (including on non-working days). Refer to IND-37 for the Indian Council of Medical Research (ICMR)'s EC Serious Adverse Event Reporting Format (Clinical Trials).

Chapter I (2), Chapter V (25), Chapter VI (42), and Third Schedule (2-3 and Tables 4-5)

2.6, 5.3, 7.1, and Glossary

Chapter 8

Progress Reporting

Last content review/update: June 16, 2023

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

2.8

5.12 and 5.13

Chapter 11 (Article 11.8)

Part C (Division 5 (C.05.012 and C.05.013))

Last content review/update: February 2, 2023

Interim and Annual Progress Reports

As described in the 2019-CTRules and IND-31, the Drugs Controller General of India (DCGI), who heads the Central Drugs Standard Control Organization (CDSCO), requires the sponsor (also known as applicant) to submit a six (6)-month status report for each clinical trial electronically via the CDSCO’s SUGAM portal (IND-59). The report should clarify whether the trial is ongoing, completed, or terminated. In the case of termination, detailed reasons for such termination must be communicated to the DCGI within 30 working days of the termination. In addition, per the 2019-CTRules, an ethics committee (EC) may periodically request study progress reports from the investigators.

As delineated in the 2019-CTRules, sponsors are also required to submit an annual status report for the clinical trial to the DCGI.

The 2019-CTRules further specifies that in cases where trials have been prematurely discontinued for any reason, including a lack of commercial interest in pursuing the new drug application (NDA), the sponsor should submit a summary report within three (3) months. The summary report should provide a brief description of the study, the number of participants exposed to the drug, dose/duration of exposure, details of adverse drug reactions, if any, and the reason for the study’s discontinuation or non-pursuit of the NDA.

See IND-35 for a Checklist of Notification for Annual Status Report documentation requirements to be included in a global clinical trial application.

Final Report

The final report should comply with the format and content guidelines listed in the 2019-CTRules as follows:

Title page
Study synopsis (1 to 2 pages)
List of abbreviations and definitions
Table of contents
EC approval letter(s)
Study team introduction
Study objective
Investigational plan
Trial participants
Efficacy evaluation
Safety evaluation
Discussion and overall conclusion
List of references
Appendices

See the 2019-CTRules for more detailed information on preparing the final report.

See also IND-35 for a checklist of documentation requirements to be included in a global clinical trial application pertaining to end of clinical trial notification.

Chapter III (11), Chapter V (25), First Schedule (6), and Third Schedule (3 and Table 6)

36

Checklist of Notification for Annual Status Report; Checklist for Notification for End of GCT

Definition of Sponsor

Last content review/update: June 16, 2023

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

2.1

5.1 and 5.5

Part C (Division 5 (C.05.001, C.05.005, C.05.015))

Last content review/update: February 2, 2023

As per the 2019-CTRules and the G-ICMR, a sponsor (also known as applicant) is defined as an individual, a company, or an institution that takes responsibility for the initiation, management, or financing of a clinical study. The G-ICMR further states that an investigator who independently initiates and takes full responsibility for a trial automatically assumes the role of a sponsor. The 2019-CTRules also indicates that the sponsor may appoint a contract research organization (CRO).

Chapter I (2)

4.0-4.2, 4.8, and 4.10

Site/Investigator Selection

Last content review/update: June 16, 2023

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 to represent the sponsor, and sign and date the application and the clinical trial attestation form.

Data and Safety 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 and the G-CanadaCTApps, 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, 5.6, and 5.23

2.1 and 2.7.2

5.5

Chapter 11 (Article 11.7)

Part C (Division 5 (C.05.005))

Last content review/update: February 2, 2023

Overview

As stated in the 2019-CTRules, all investigators must possess appropriate qualifications, training, and experience, and should conduct the trials in compliance with Good Clinical Practices (GCPs) and Good Laboratory Practices. (See GCLP for the G-ICMR for Good Clinical Laboratory Practices, IND-31 for additional laboratory requirement information, and IND-40 and IND-30 for international Good Laboratory Practice guidelines.) Investigators should also have access to investigational and treatment facilities as relevant to the protocol.

Per the 2019-CTRules, prior to entering into an agreement with the investigator(s)/institution(s) to conduct a study, the sponsor (also known as applicant) should provide the involved parties with the protocol and an up-to-date investigator’s brochure and allow them sufficient time to review this documentation. The sponsor must also define and allocate all study-related duties and responsibilities to the respective identified person(s) and organization(s) prior to initiating the study.

In addition, per Notice2Dec19, the Central Drugs Standard Control Organization (CDSCO) is preparing a comprehensive database of clinical trial sites and investigators involved in the conduct of global clinical trials in different therapeutic categories by collecting information from various sources. The first phase includes an Excel spreadsheet of sites and investigators involved in global clinical trials (IND-26).

See also IND-28 for the Indian Council of Medical Research (ICMR)’s research conduct policies.

Foreign Sponsor Responsibilities

No information is currently available on foreign sponsor responsibilities.

Data and Safety Monitoring Board

While there are no general requirements for establishing a Data Safety Monitoring Board (DSMB), the G-Children recommends that a DSMB be strongly considered for research involving children in emergency situations.

Multicenter Studies

As delineated in the G-ICMR, in the case of multicenter research studies, all of the participating study sites are required to obtain approval from their respective ethics committees (ECs). The study sites also typically follow a common protocol to avoid duplication of effort, wastage of time, and communication issues. See the G-ICMR for additional participating site requirements when a primary EC is selected for common EC review. Also, see the Scope of Review section for additional details.

Further, per the G-ICMR, if a multicenter trial is going to be conducted, the sponsor may organize a coordinating committee or select coordinating investigators. The sponsor must also conduct training for investigators in ethics, GCPs, standard operating procedures (SOPs), and study protocols.

6.5

4.2.3, 4.8 (Table 4.2.3), and 4.10

Chapter III (11), Third Schedule (1, 3, and Table 4)

Insurance & Compensation

Last content review/update: June 16, 2023

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 further 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.

Policies, Guidelines, and Resources, Consent Process (Consent Form Template)

4.8 and 5.8

Chapter 3 (Article 3.2)

Last content review/update: February 2, 2023

Insurance

The G-ICMR specifies that the sponsor (also known as applicant) should provide insurance coverage or a provision in the budget for possible compensation for trial-related injuries. The G-ICMR also states that it is preferable to have the insurance certificate and the policy for study participants. Further, the policy should explain the conditions of coverage, date of commencement, and expiration date for risk coverage (if applicable). In addition, institutional mechanisms must be established to allow for insurance coverage of trial-related or unrelated illnesses (ancillary care).

The 2019-CTRules states that the ethics committee (EC) also requires a copy of the insurance policy or details regarding compensation for participation and for serious adverse events (SAEs) occurring during the study as part of its submission review process. IND-60 provides a table of the different policy types available in India including no fault compensation, the claims-made policy, and the premium rating policy. Regarding coverage limits, IND-60 further indicates there is no set rule for establishing coverage limits or minimums in India; however, the consensus in the insurance community is that a clinical trials liability policy should carry a minimum limit of $1 million and can have upper limits of $10 million through $20 million or more. See IND-60 for additional information on policy types and coverage limits.

With regard to indemnity coverage, the G-ICMR states that an indemnity policy must be included in the documentation for EC review. The policy should clearly indicate the conditions of coverage, date of commencement, and coverage expiration date, if applicable.

Compensation

Injury or Death

In accordance with the 2019-CTRules and the G-ICMR, the sponsor is responsible for providing compensation to research participants and/or their legal heir(s) in the event of trial-related injuries, permanent disability, or death. Per the G-ICMR, in the event the investigator/institution becomes the sponsor in a clinical trial, it is the host institution’s responsibility to provide compensation for research-related injury or harm as determined by the ethics committee (EC).

Per the 2019-CTRules and the G-ICMR, the sponsor must also ensure that participants who suffer any trial-related injuries be provided with free medical treatment for such injuries as long as required per the opinion of the investigator (and the EC per the G-ICMR), or until such time it is established that the injury is not related to the clinical trial, whichever is earlier. Per the 2019-CTRules, if the sponsor or the representative fails to provide medical management, the Drugs Controller General of India (DCGI), after a hearing, must issue a written order to suspend or cancel the study or restrict the sponsor, including the representative, from conducting any further clinical trials or taking any other action for such period deemed appropriate for this case. (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

The 2019-CTRules further notes that the sponsor is responsible for compensating the research participant and/or the legal heir(s) if the trial-related injury, death, or permanent disability to a participant is specifically related to any of the following reasons:

Adverse effects of an investigational product (IP)
Any trial procedures involved in the study
A violation of the approved protocol, scientific misconduct, or negligence by the sponsor, the representative, or the investigator
Failure of the IP to provide the intended therapeutic effect where, the standard care, though available, was not provided to the participant per the protocol
Not providing the required standard care, though available to the participant per the protocol in the placebo-controlled trial
Adverse effects due to concomitant medication excluding standard care, necessitated as part of the approved protocol
Adverse effect on the child in-utero due to a parent’s participation in a trial
Any clinical trial procedures involved in the study leading to a serious adverse event (SAE/serious adverse drug reaction (SADR)

According to IND-31, compensation and medical management requirements are also applicable in the case of injury or death occurring during an academic trial.

In the case of a trial-related injury, the 2019-CTRules and IND-31 state that the sponsor is required to provide complete medical management and compensation to the participant within 30 days of receiving an order from the DCGI. In the event of permanent injury or death, the sponsor is required to provide compensation to the participant or to the legal representative(s) or guardian(s) within 30 days of receiving the DCGI’s order.

The 2019-CTRules explains that in the case of an SAE resulting in death, the DCGI must constitute an independent expert committee to review the incident and make its recommendations to the DCGI for the cause of death and to provide a quantum of compensation. The sponsor or the representative and the investigator must forward their reports, after due analysis, to the DCGI and the head of the institution where the trial was conducted within 14 days of the occurrence. The EC must forward its report along with its opinion on financial compensation, if any, to be paid by the sponsor or the representative within 30 days of receiving the investigator’s report. The DCGI, in turn, must forward the sponsor, investigator, and EC reports to the expert committee chairperson. Following its review, the expert committee must make its recommendations to the DCGI as to the cause of the SAE resulting in death and the quantum of compensation within 60 days from receiving the DCGI’s submission. The DCGI must then consider the expert committee’s recommendations and issue an order within 90 days to the sponsor or the representative specifying the quantum of compensation he/she is required to pay within 30 days of receiving the order.

In the case of an SAE/SADR resulting in permanent disability or any injury other than death, the 2019-CTRules indicates that the sponsor or the representative and the investigator must forward their reports, after due analysis, to the DCGI, the EC chairperson, and the head of the institution where the trial has been conducted within 14 days of the occurrence. The EC, after due analysis, must forward its report along with its opinion on financial compensation, if any, to the DCGI within 30 days of the event occurrence. The DCGI, in turn, must determine the cause of the injury and issue an order, with the option to constitute an independent expert committee, within 60 days of receipt of the report. The DCGI must issue an order within 90 days of receiving the report indicating the quantum of compensation to be paid by the sponsor or the representative within 30 days of receipt of this order.

In the case of an injury not being permanent in nature, per the 2019-CTRules, compensation should be commensurate with the participant’s loss of wages.

Per the 2019-CTRules, in the event that a sponsor or the representative fails to provide compensation to a research participant for trial-related injuries, or to the legal heir(s) in case of death, the DCGI must, after giving an opportunity to show cause why such an order should not be passed by a written order, suspend or cancel the clinical trial, or restrict the sponsor or the representative from conducting any further clinical trials in India or taking any other action deemed fit given the circumstances.

See the 2019-CTRules and the G-ICMR for detailed information on terms of compensation payment.

Trial Participation

The G-ICMR explains that participants may also be compensated for their time and other expenses (e.g., loss of wages, food supplies, and travel). The EC should approve all payments, reimbursement, and medical services provided. Per the G-ICMR, participants should not be required to pay for any expenses incurred beyond routine clinical care and those that are research related including patient work-ups, or interventions associated with treatment, and if applicable, participants may receive additional medical services at no further cost.

Post-Trial Access

The 2019-CTRules and IND-31 explain that the investigator may recommend the sponsor provide post-trial access to the investigational product (IP) free of cost to the participant for such period as deemed necessary by the investigator and the EC. The sponsor must obtain DCGI approval to initiate this plan. The investigator’s recommendation will be based on the following conditions:

If the trial is being conducted for an indication for which no alternative therapy is available, and the IP has been determined to be beneficial
The participant and/or the legal representative(s) or guardian(s) has consented in writing to use the post-trial IP, and has certified and declared in writing, along with the investigator, that the sponsor must have no liability for post-trial use of the IP

See also IND-6 for additional information on post-trial access to IPs under the 2019-CTRules.

Post-Trial Access

12, 39-41, and 61

Current Scenario of Liability and Indemnity in India and Other Countries

2.5-2.7, 4.7, 4.8, Box 4.4(A), 7.1, and 7.16

Chapter I (2), Chapter V (25 and 27), Chapter VI (39-40 and 42), Third Schedule (3, Table 1 and Table 3), and Seventh Schedule

Risk & Quality Management

Last content review/update: June 16, 2023

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.

As indicated in the CA-ICH-GCPs, he 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.

Monitoring 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 their 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.

Purpose and Scope, and Glossary

5.0-5.2, 5.18, 5.19, 5.21, and 6.10

5.10 and 5.15

Part C (Division 5 (C.05.007-008, C.05.010, and C.05.015))

Last content review/update: February 2, 2023

Quality Assurance/Quality Control

In accordance with the 2019-CTRules and the G-ICMR, the sponsor (also known as applicant) 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, Good Clinical Practices (GCPs), and all applicable laws and regulations.

Monitoring Requirements

As per the 2019-CTRules, the sponsor must permit clinical trial site inspections by the Drugs Controller General of India (DCGI)-authorized officers. The officers may enter the premises and clinical trial site with or without prior notice to inspect, search, or seize any record, statistical result, document, investigational drug, and other related material. The sponsor must also reply to inquiries raised by the inspecting authority in relation to the conduct of the trial. (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

In addition, as part of its QA system, the 2019-CTRules notes that investigator(s) may provide periodic study progress reports (PSUR), or regulatory officials or sponsor-designated authorized representatives may provide monitoring and internal audit reports to the ethics committee (EC) to support its recurring clinical trial reviews. An audit certificate may be issued, if available.

Furthermore, the 2019-CTRules requires the investigator to sign an undertaking indicating agreement to maintain adequate and accurate records and to make those records available for audit or inspection by the sponsor, the EC, the Central Licensing Authority, or their authorized representatives, in accordance with regulatory provisions and GCP guidelines. The investigator must agree to fully cooperate with any study-related audit conducted by regulatory officials or authorized representatives of the sponsor.

See IND-35 for a checklist of PSUR documentation requirements to be included in a global clinical trial application, and IND-34 for the DCGI’s GCP Inspection Checklist.

Premature Study Termination/Suspension

As delineated in the 2019-CTRules, when the sponsor fails to comply with any provisions of the DCA-DCR and the 2019-CTRules, the DCGI may, after giving an opportunity to show cause and after affording an opportunity of being heard, by an order in writing, implement one (1) or more of the following actions:

Issue a warning in writing describing the deficiency or defect observed during inspection or otherwise which may affect adversely the right or well-being of a trial participant or the validity of clinical trial conducted
Reject the results of the clinical trial
Suspend for such period as considered appropriate or cancel the permission granted in Form CT-06 or in Form CT-4A
Debar the investigator or the sponsor, including the representatives, from conducting any clinical trial in the future for such period as considered appropriate by the DCGI

The sponsor or the representative may appeal the DCGI’s decision within 60 working days of receipt of the order.

Further, per the 2019-CTRules, in case of studies prematurely discontinued for any reason, including lack of commercial interest in pursuing the new drug application, the sponsor should submit a summary report within three (3) months. The summary report should provide a brief description of the study, the number of patients exposed to the drug, dose and duration of exposure, details of adverse drug reactions, if any, and the reason for discontinuation of the study or non-pursuit of the new drug application.

See IND-35 for a checklist of premature study termination documentation requirements to be included in a global clinical trial application.

4.2.3, 4.10, and 6.1 (Table 6.1)

Chapter V (29-30), Third Schedule, and Eighth Schedule (Forms CT-4A and CT-06)

Data & Records Management

Last content review/update: June 16, 2023

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 standard operation procedures (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 Health Canada (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. Per the G-FDR-0100, sponsors may also be required to maintain records under provincial law, institutional policies, and contractual agreements with investigators, ethics committees (ECs), or others. Where it is not possible to comply with both sets of requirements, the CanadaFDR would govern and the records must be maintained for 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 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.

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.

1.65, 5.5, 6.10, and 8

5.12

Part C (Division 5 (C.05.012))

Regulatory Impact Analysis Statement

Last content review/update: February 2, 2023

Electronic Data Processing System

No information is currently available on electronic data processing systems.

Records Management

Per the 2019-CTRules, the sponsor (known as applicant) must keep a record of new drugs manufactured and persons to whom the drugs have been supplied for clinical trial or bioavailability and bioequivalence study or for examination, testing, and analysis. In addition, the 2019-CTRules indicates that the licensed sponsor must maintain records of any imported new drug or substance that indicates the quantity of drug imported, used, and disposed of in any manner including related documentation.

Chapter VIII (55) and Chapter IX (70)

Personal Data Protection

Last content review/update: June 16, 2023

Responsible Parties

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs), states that where researchers seek to collect, use, share, and access different types of information or data about participants, they should determine whether the information or data proposed in research may reasonably be expected to identify an individual. Researchers and ECs must consider whether information is identifiable or non-identifiable.

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 PrivAct covers the personal information-handling practices of federal government departments and agencies in Canada, and the PIPEDA 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.

Per the G-TCPS2, in the research context, the most simplified method to protect participants is through the collection and use of anonymous or anonymized data. When anonymized data is not possible or desirable, a next best alternative is to use de-identified data, which is provided to the researcher in de-identified form and the existing key code is accessible only to a custodian or trusted third party who is independent of the researcher. Where it is not feasible to use anonymous or anonymized data for research, the ethical duty of confidentiality and the use of appropriate measures to safeguard information become paramount. Researchers should consult their ECs if they are uncertain about whether information proposed for use in research is identifiable (e.g., when proposing to link anonymized or coded data sets).

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.

Chapter 2 (Article 2.1) and Chapter 5 (A. Key Concepts)

Part I (2, 6.1, and 7)

3, 7, and 8

Last content review/update: February 2, 2023

Responsible Parties

For the purposes of data protection regulation in India, the ITAct, the ITActAmend, and the IT-SPDIRules delineate responsibilities of the “body corporate.” The body corporate as defined by the ITAct, the ITActAmend, and the IT-SPDIRules refers to any company including a firm, sole proprietorship, or other association of individuals engaged in commercial or professional activities. The IT-SPDIRules further explains that the body corporate or any person on its behalf is the entity responsible for collecting, receiving, possessing, storing, dealing with, or handling personal information, including sensitive personal data and information. (Note: In ClinRegs, the “body corporate” is referred to as “sponsor,” but the requirements may apply to other parties as well).

Data Protection

Data protection in India is currently regulated by the ITAct, the ITActAmend, and the IT-SPDIRules. Per the IT-SPDIRules, the sponsor (or the “body corporate”) must provide a privacy policy for the handling of or dealing with this personal information including sensitive personal data or information. The IT-SPDIRules defines sensitive personal data or information as information relating to password(s); financial information; physical, physiological, and mental health condition(s); sexual orientation; medical records and history; and biometric information. The sponsor must ensure that this policy is available for view by the information providers under a lawful contract. The policy must be published on the sponsor’s or its representative’s website and provide the following:

Clear and easily accessible statements of its practices and policies
The type of personal information including sensitive personal data or information collected
The purpose of collection and usage of such information
Disclosure of information including sensitive personal data or information
Reasonable security practices and procedures

Please refer to the IT-SPDIRules for detailed requirements on implementing security practices and procedures and collecting, disclosing, and transferring sensitive personal data or information.

See also IND-65 for more detailed information on India’s data protection requirements.

Consent for Processing Personal Data

As set forth in the IT-SPDIRules, the body corporate or its representative must obtain consent in writing through letter, fax, or email from the provider of the sensitive personal data or information regarding the purpose of usage before collection of such information. The IT-SPDIRules further states that while collecting information directly from the information provider, reasonable steps must be taken to ensure that the information provider receives details regarding the following:

The fact that the information is being collected
The purpose for which the information is being collected
The intended recipients of the information; and
The name and address of the agency that is collecting the information, and the agency that will retain the information

Per the IT-SPDIRules, the body corporate or its representative, must provide an option to the information provider to withhold the requested data or information prior to the collection of information including sensitive personal data or information. The information provider must, at any time, also have the option to withdraw consent given earlier to the sponsor or the sponsor’s representative. This withdrawal of consent must be sent in writing.

2-5

Chapter IX (43A)

Part II (22)

Documentation Requirements

Last content review/update: June 16, 2023

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 the 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 the 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 the 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 a continuous duty to provide participants with all information relevant to their ongoing consent to participate in the research. Consent begins with the initial contact (e.g., recruitment) and carries through to the end of participation in the study. Throughout the clinical trial, researchers have a continuous responsibility to provide participants and ECs with all information relevant to participants’ ongoing consent to participate in the research. The researcher also must notify participants of any changes to the research project that may affect them. These changes may have ethical implications, may be relevant to their decision to continue in the study, or may be unique to the particular circumstances of individual participants. Specifically, researchers must disclose changes to the risks or potential benefits of the research. Change in participant capacity is an important element of ongoing consent. Rather than an age-based approach to consent, researchers should use an approach based on decision-making capacity in compliance with any laws governing research participation. This includes those whose decision-making capacity is in the process of development, those whose decision-making capacity is diminishing or fluctuating, and those whose decision-making capacity remains only partially developed. Mechanisms should be in place from the outset to identify and address any changes that could affect consent. 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 G-TCPS2, the CA-ICH-GCPs, and CAN-35, the participant and/or the 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 the 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 the legal representative(s) and/or guardian(s)
The participant and the 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 the 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 the legal representative(s) and/or guardian(s) to waive or appear to waive the participant’s 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 can use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (e.g., 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 change 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 exact nature and extent of any proposed alteration is defined
There is a plan to brief participants and offer the option of refusing consent and/or withdrawing data and/or human biological materials

Policies, Guidelines, and Resources; Consent Process (Key Considerations)

4.8, 8.2, and 8.3

5.5, 5.6, 5.8, and 5.10

Chapters 3 and 10

Part C (Division 5 (C.05.005, C.05.006, C.05.008, and C.05.010))

Last content review/update: February 2, 2023

Obtaining Consent

In all Indian clinical trials, a freely given, written informed consent is required to be obtained from each participant to comply with the requirements set forth in the 2019-CTRules, the G-ICMR, and the G-Children.

As per the 2019-CTRules and the G-ICMR, prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) approval for the informed consent form (ICF) and the patient information sheet. This documentation must also be supplied to the Drugs Controller General of India (DCGI), prior to the trial’s initiation. The ICF and patient information sheet are ultimately integrated into one (1) document referred to as the ICF. (See the Required Elements section for details on what should be included in the form.) (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

The 2019-CTRules, the G-ICMR, and the G-Children specify that investigator(s) should provide detailed study information to the research participant and/or the legal representative(s) or guardian(s). The ICF content should be briefly and clearly presented orally, and in writing, and in a manner that is easy to understand, commensurate with the comprehension level of the participants, and without coercion or unduly influencing a potential participant to enroll in the trial. Per the G-ICMR, the ICF language should not only be scientifically accurate and simple, but should also be sensitive to the participant’s social and cultural background. In addition, the participant and/or the legal representative(s) or guardian(s), should be given adequate time to consider whether to participate. The consent should also be given voluntarily and not be obtained under duress or coercion of any sort or by offering any inducements.

The G-ICMR also states that, in the case of differently abled participants, such as those with physical, neurological, or mental disabilities, appropriate methods should be used to enhance the participants’ understanding (e.g., Braille for the visually impaired).

As delineated in the 2019-CTRules, investigator(s) must obtain an audio-video (AV) recording of the informed consent process for vulnerable participants in clinical trials for a new chemical or molecular entity, including the procedure of providing information to the participant and his/her understanding of the consent. This AV recording should be retained in the investigator’s files. In cases where clinical trials are conducted on anti-human immunodeficiency virus (HIV) and anti-leprosy drugs, the investigator(s) must only obtain an audio recording of the informed consent process. The investigator(s) is also required to retain the audio recording for his/her records.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Re-Consent

According to the G-ICMR and the G-Children, investigator(s) are required to renew the informed consent of each participant if there are any changes in the ICF related to the study conditions or research procedures, or if new information becomes available during the trial.

Per the G-ICMR and the G-Children, re-consent is applicable in cases in which a participant regains consciousness from an unconscious state and/or recovers mental capacity to understand the research study. If such an event is expected, then procedures to address this circumstance should be explained clearly in the ICF.

The G-ICMR and the G-Children explain that re-consent is required in the following situations:

New information pertaining to the study becomes available that has implications for the participant(s) or that changes the benefit and risk ratio
A research participant who is unconscious regains consciousness or suffered loss of mental competence and regains the ability to understand the research implications
A child becomes an adult during the course of the study, or the legal representative(s) or guardian(s) have changed
Research requires a long-term follow up or an extension
There is a change in treatment modality, procedures, site visits, data collection methods, or tenure of participation which may impact a participant’s decision to continue in the research
There is possibility of identity disclosure through data presentation or photographs (this should be camouflaged adequately) in an upcoming publication
Future research may be carried out on stored biological samples if not anonymized

The partner/spouse may also be required to give additional re-consent in some of the above cases.

Language Requirements

As stated in the 2019-CTRules and the G-ICMR, the ICF should be written in English and/or in a vernacular language that the participant is able to understand.

Documenting Consent

The G-ICMR and the G-Children specify that the participant and/or the participant’s legal representative(s) or guardian(s) must sign and date the ICF. If the participant is incapable of giving an informed consent, the legal representative(s) or guardian(s) should sign and date the ICF. Where the participant and/or the legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Per the G-ICMR, if the participant and/or the legal representative(s) or guardian(s) cannot sign, a thumb impression must be obtained. In addition, the investigator(s) who administers the consent should also sign and date the ICF. As stated in the G-ICMR and the G-Children, when written consent as a signature or thumb impression is not possible, verbal consent may be taken with the EC’s approval, in the presence of an impartial witness who should sign and date the consent document, or through an AV recording. Per the G-ICMR, the ICF may also be administered and documented electronically, as long as the EC approves the process first.

As described in the G-ICMR, the following special situations may also arise in administering consent:

The gatekeeper’s (a group’s head/leader or the culturally appropriate authorities), may provide permission on the group’s behalf in writing or audio/video recording and be witnessed
Community consent is required for certain populations in order for participants to be permitted to participate in the research

According to the G-ICMR and the G-Children, a copy of the signed ICF and the patient information sheet should be given to the participant or the legal representative(s) or guardian(s). Per the G-Children, the investigator should also keep a signed copy of the ICF.

Waiver of Consent

As specified in the G-ICMR and the G-Children, the investigator(s) can apply to the EC for a waiver of consent if the research involves less than minimal risk to participants and the waiver will not adversely affect the rights and welfare of the participants. In addition, per the G-ICMR, the EC may grant a waiver of consent in the following situations:

Research cannot practically be carried out without the waiver and the waiver is scientifically justified
Retrospective studies, where the participants are de-identified or cannot be contacted
Research on anonymized biological samples/data
Certain types of public health studies/surveillance programs/program evaluation studies
Research on data available in the public domain, or
Research during humanitarian emergencies and disasters, when the participant may not be in a position to give consent. An attempt should be made to obtain the participant’s consent as soon as possible

Refer to the Children/Minors section for information on waivers involving children.

See the G-ICMR, IND-5, and IND-27 for additional information on informed consent requirements.

Chapter III (11) and Third Schedule (2-3 and Tables 1 and 3)

3.1

7.11 and Annexures I, II, and III

2.2, 4.4, 4.8, 5.0, 5.2-5.4, and 5.8

4, 11.2, and Annexures I and II

5

3-6

Required Elements

Last content review/update: June 16, 2023

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 sources 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 the 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 can be found in CAN-35.

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

Policies, Guidelines, and Resources, and Consent Process (Sample consent forms)

4.8

Chapter 3

Last content review/update: February 2, 2023

Per the 2019-CTRules, the G-ICMR, and the G-Children, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: The regulatory sources 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 nature and purpose
The expected duration of the participant's participation
Any benefits reasonably expected from the research to the participant or others; if no benefit is expected, the participant should be made aware of this
The disclosure of specific appropriate alternative procedures or therapies available to the participant
The mechanism by which confidentiality of records identifying the participant will be maintained and who will have access to the participant’s medical records
An explanation about whom to contact for trial-related queries, participant rights, and in the event of any injury
The policy on compensation and/or medical treatment(s) available to the participant in the event of a trial-related injury, disability, or death
Participation is voluntary, the participant can withdraw from the study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled
Any reasonably foreseeable risks or discomforts to the participant resulting from participation
Approximate number of participants enrolled in the study

Additional requirements listed in the G-ICMR and the G-Children include:

Foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research (e.g., storage period of sample/data; probability of material being used for secondary purposes; whether material is to be shared with others; participant’s right to prevent use of his/her biological sample(s) at any time during or after the study; risk of discovery of biologically sensitive information and provisions to safeguard confidentiality)
Publication, if any, including photographs and pedigree charts
Payment/reimbursement for participation and incidental expenses depending on the type of study
Insurance coverage, if any, for research-related or other adverse events
If there is a possibility that the research could lead to any stigmatizing condition (e.g., HIV and genetic disorders, provision for pre-test and post-test counseling)
Post-research plan/benefit sharing for biological material research and/or if data leads to commercialization

Additional requirements listed in the 2019-CTRules include:

The procedures to be followed, including all invasive procedures
The investigational product (IP) may fail to achieve the intended therapeutic effect
In the case of a placebo-controlled trial, the placebo administered to the participant(s) must not have any therapeutic effect
The anticipated prorated payment, if any, to the participant for participating in the trial
The participant’s responsibilities in participating in the trial
Foreseeable circumstances under which the investigator(s) may remove the participant without consent
The consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
The participant and/or the legal representative(s) or guardian(s) will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue
The particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant), which are currently unforeseeable
Additional costs to the participant that may result from participating in the study
Any other pertinent information
Clinical trial treatment schedule(s) and the probability for random assignment to each treatment

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

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Second Schedule (1) and Third Schedule (2-3 and Tables 1 and 3-4)

3.1

7.11 and Annexures I, II, and III

2.2, 5.0-5.3, and 6.11

4, 11.2, and Annexures I and II

Participant Rights

Last content review/update: June 16, 2023

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 the legal representative(s) or guardian(s) should be informed that participation is voluntary, that they 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, participants should be assured that their participation is completely voluntary, they are under no obligation to participate, and they 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 the 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 the legal representative(s) or guardian(s) should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or the participant’s 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 their 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.

Consent Process (Consent Form Template)

1.27, 3.1, and 4.8

5.1 and 5.5

Chapter 1 (Article 1.1), Chapter 2, and Chapter 3 (Articles 3.1 and 3.2)

Part C (Division 5 (C.05.001 and C.05.005))

Last content review/update: February 2, 2023

Overview

In accordance with the 2019-CTRules and the G-ICMR, India’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-ICMR upholds the Declaration of Helsinki (IND-63). The 2019-CTRules, the G-ICMR, and the G-Children state 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 stated in the 2019-CTRules, the G-ICMR, and the G-Children, the participant and/or the legal representative(s) or guardian(s) should be informed that participation is voluntary, the participant may withdraw from the research study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As per the 2019-CTRules, the G-ICMR, and the G-Children, a potential research participant and/or the 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

As described in the 2019-CTRules, the G-ICMR, and the G-Children, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The 2019-CTRules also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

The 2019-CTRules, the G-ICMR, and the G-Children state that the research participant and/or the legal representative(s) or guardian(s) should be provided with contact information for the investigator(s) and the ethics committee (EC) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

The Right to Safety and Welfare

The G-ICMR clearly states that a research participant’s right to safety and protection of health and welfare must take precedence over the interests of science and society.

See the G-ICMR and IND-27 for additional information on informed consent requirements.

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

Chapter III (7 and 11), Chapter V (28) and Third Schedule (3)

3.1

1.0, 1.1, 2.2, 2.3, 4.0, 5.0-5.2, and 7.1

1 and 5

Emergencies

Last content review/update: June 16, 2023

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 the 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 (REB) in Canada) must approve the protocol in advance. The participant and/or the 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 the 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 the 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 2, 2023

Children in Emergency Situations

Per the G-Children, research involving children in emergency situations should only be carried out when it is scientifically justified and cannot be conducted outside this setting. The ethics committee(s) (EC) should review and approve these studies as well as the proposed timeframe in which formal consent will be obtained. If consent cannot be obtained in an emergency situation, deferred consent is suggested. Deferred consent involves giving minimum information verbally, followed by full details and formal consent later. If the legal representative(s) or guardian(s) are unavailable or unable to give consent, another individual, such as the participant’s doctor or a person nominated by the healthcare provider, can give consent. However, the doctor or a person nominated by the healthcare provider may not be involved in the research. It is recommended that a Data Safety Monitoring Board (DSMB) be strongly considered for these types of studies. See the Children/Minors section for additional pediatric informed consent requirements.

Moreover, per the G-Children, if a child’s legal representative(s) or guardian(s) refuses to give consent once their child is stabilized, he/she should not be included in the research, and no further research related procedures/data collection should be done. Additionally, the previously collected data obtained prior to the consent process should not be used without the legal representative(s)’s or guardian(s)’s permission.

Humanitarian Emergencies

As explained in the G-ICMR, during a humanitarian emergency or disaster, close attention should be paid to the effect of the emergency on perceptions of ethical questions, altered or increased vulnerabilities, provider-patient and researcher-participant relationships, and issues related to integrity of studies and ethical review processes. Obtaining valid informed consent in humanitarian emergencies is a challenge as the decisional capacity of the participants would be so low that they may not be able to differentiate between reliefs offered and research components. This should be very clearly distinguished during the informed consent process. Additional safeguards are required for participants due to their vulnerability, for example, counseling, psychological help, medical advice, and process of stakeholder consultation.

In addition, the G-ICMR indicates that the potential research participants might be under duress and traumatized. Researchers should be sensitive to this situation and are obligated to ensure that the informed consent process is conducted in a respectful manner. Researchers should strive to identify and address barriers to voluntary informed consent and not resort to inducements for research participation. The different roles of researchers, caregivers and volunteer workers must always be clarified, and potential conflict of interest declared. If research involves vulnerable individuals (such as minors), then the legal representative(s) or guardian(s) should give consent. Additional protections might be required in special cases, for example, children with untraceable or deceased relatives. In these situations, consent should be obtained from an individual who is not part of the research team who should be designated by the institution/agency conducting research.

For seeking a waiver of consent, the researchers should give the rationale justifying the waiver. The EC should approve such a waiver after careful discussion on the issue. Refer to the Documentation Requirements section for additional information on waivers of consent. When consent of the participant or the legal representative(s) or guardian(s) is not possible due to the situation, informed consent must be administered to the participant or the legal representative(s) or guardian(s) at a later stage, when the situation allows. However, this should be done only with the prior approval of the EC. See IND-5 for additional information on consent requirements during medical emergencies.

12

3.1 and 6.5

12.0, 12.2, and 12.5

Vulnerable Populations

Last content review/update: June 16, 2023

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 2, 2023

Overview

As set forth in the 2019-CTRules and the G-ICMR, in all 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 G-ICMR further describes vulnerable groups and individuals as those who may have an increased likelihood of incurring additional harm, as they may be relatively (or absolutely) incapable of protecting their own interests. According to the G-ICMR, vulnerable populations are characterized as individuals/communities with hierarchical relationships (e.g., prisoners, armed forces personnel, or staff and students at medical, nursing, or pharmacy academic institutions); economically and socially disadvantaged individuals (e.g., persons who are unemployed, abandoned, orphans, have language barriers, or cultural differences); persons below the poverty line; ethnic, religious, or sexual minority groups; tribal and marginalized communities; terminally ill patients or those suffering from stigmatizing or rare diseases; patients in emergency situations; institutionalized persons; homeless persons, nomads, or refugees; minors; women in special situations (e.g., pregnant or lactating women, those with poor decision-making powers, or poor access to healthcare); those with mental illness and cognitively impaired, differently abled, or mentally or physically disabled; or others incapable of personally giving consent.

See the G-ICMR for detailed safeguards that must be complied with when trials involving vulnerable populations are conducted. The G-ICMR also describes research principles that must be upheld during these trials and upholds the Declaration of Helsinki (IND-63).

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations. See also IND-5 for additional information on consent requirements for vulnerable populations.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

Terminally Ill Patients

Per the G-ICMR, terminally ill patients or patients seeking new treatments are vulnerable as they are ready to give consent for any intervention that could help them. The EC should carefully review protocols and recruitment procedures for these studies and comply with the following requirements:

Additional monitoring should be done to detect any adverse event as soon as possible
A benefit-risk assessment should be performed that considers the potential participant’s perception of benefits and risks
Post-trial access to the medication

Indigenous Peoples

The G-ICMR states that research on tribal populations should only be conducted if it is of a specific therapeutic, diagnostic, and preventative nature with appropriate benefits to the tribal population. A competent administrative authority’s approval, such as the tribal welfare commissioner or the district collector, should be obtained prior to an investigator entering the area. Whenever possible, it is desirable to seek the help of government functionaries/local bodies or registered, non-governmental organizations who work closely with the tribal groups and have their confidence. The tribal leader, or other culturally appropriate authority may serve as the gatekeeper from whom permission to enter and interact should be obtained. A participant’s consent should be taken along as well as consulting with community elders and individuals who know the local language/dialect of the tribal population, and in the presence of appropriate witnesses. Additional precautions should be taken to avoid including children, pregnant women, and elderly people belonging to particularly vulnerable tribal groups. Benefit sharing with the tribal group should also be ensured for any research done using tribal knowledge that may have the potential for commercialization.

Elderly Persons

Permission to conduct clinical trials in geriatric patients must comply with the requirements listed in the Required Elements section. According to 2019-CTRules, geriatric patients should be included in Phase II and Phase III clinical trials at the sponsor’s (also known as the applicant’s) recommendation, in the following circumstances:

The disease intended to be treated is typically a disease of aging
The population to be treated is known to include substantial numbers of geriatric patients
There is specific reason to expect that conditions common in the elderly are likely to be encountered
The new drug is likely to alter the geriatric patient’s response (with regard to safety or efficacy) compared with that of the non-geriatric patient

Persons in Dependent Groups

As indicated in the G-ICMR, while reviewing protocols involving participants who are engaged in subordinate or dependent relationships, the ethics committee (EC) must ensure the following:

Participant enrollment is specifically relevant to the research questions and is not merely a matter of convenience
Extra efforts are required to ensure the autonomy of these individuals is respected, and that they are able to freely decide to participate or deny consent and/or later withdraw from the study without fear of any negative repercussions on their care
Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol

Sexual Minorities and Sex Workers

Per the G-ICMR, sexual minorities and sex workers require additional protections as they are more vulnerable to privacy, confidentiality, stigma, discrimination, and exploitation issues during a research study. Research proposals should ensure the dignity of these participants is protected and that they have access to quality healthcare. Investigators should consult the community, if possible, prior to the proposal being finalized. It is also advised that a representative of the sexual minority group/lesbian/gay/bisexual and transgender (LGBT) community attend the EC meeting as a special invitee/member.

First Schedule (3) and Third Schedule (3)

7.11 and Annexures I, II, and III

1.1, 2.9, 6.0-6.2, 6.6-6.7, and 6.9-6.10

4, 11.2, and Annexures I and II

1, 2, and 6

Children/Minors

Last content review/update: June 16, 2023

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 the child’s 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, then affirmative assent is required to participate in a study according to the participant’s 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, see CAN-12.

Guidelines III and IV

Consent Process (Key Considerations)

4.8

1

Chapter 3 (Article 3.10) and Chapter 4 (Article 4.4)

Last content review/update: February 2, 2023

As per the G-ICMR, children are individuals who have not obtained the legal age of consent, which is 18.

As stated in the G-ICMR, the 2019-CTRules, and the G-Children, in the case of pediatric clinical trials, the participants are legally unable to provide written informed consent, and are dependent on their legal representative(s) or guardian(s) to assume responsibility for their participation in a research study.

However, as specified in the 2019-CTRules, all pediatric participants should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the informed consent form (ICF). In these studies, the following requirements should be complied with:

Written informed consent should be obtained from the legal representative(s) or guardian(s); however, all pediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand
Where appropriate, pediatric participants should additionally provide their assent to enroll in the study, and mature minors and adolescents should personally sign and date a separately designed written assent form
Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the investigator’s and legal representative(s)’s or guardian(s)’s opinion, a pediatric patient’s welfare would be jeopardized by failing to participate in the study. In this situation, continued legal representative(s) or guardian(s) consent should be sufficient to allow participation in the study

The 2019-CTRules further specifies requirements for pediatric studies involving new drugs. These studies must take into account the following issues:

The timing of new drug pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments
If the new drug is for diseases predominantly or exclusively affecting pediatric patients, clinical trial data should be generated in the pediatric population except for initial safety and tolerability data, which will usually be obtained in adults, unless such initial safety studies in adults would yield little useful information or expose them to inappropriate risk
If the new drug is intended to treat serious or life-threatening diseases, occurring in both adults and pediatric patients, for which there are currently no or limited therapeutic options, the pediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit; in circumstances where this is not possible, lack of data should be justified in detail
If the new drug has a potential for use in pediatric patients, pediatric studies should be conducted
Pediatric studies should include clinical trials, relative bioequivalence comparisons between pediatric and adult formulations, and pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used
If the new drug is a major therapeutic advance for the pediatric population, studies should begin early in the drug development, and this data should be submitted with the new drug application

The reviewing ethics committee (EC) should also include members who are knowledgeable about pediatric, ethical, clinical, and psychosocial issues.

Refer to the 2019-CTRules for detailed pediatric study requirements.

Per the G-ICMR, the EC should also perform a benefit-risk assessment to determine whether there is a need to implement additional safeguards/protections to conduct a study involving children. The EC should consider the circumstances of the children to be enrolled in the study including their age, health status, and other factors and potential benefits to other children with the same disease or condition, or to society as a whole. In addition, the G-Children should be consulted for detailed EC assessment criteria to be used to evaluate research studies involving children.

As per the G-Children, following EC approval of the protocol, the informed consent requirement for children may be waived in the following circumstances:

When it is impractical to conduct research since confidentiality of personally identifiable information has to be maintained throughout the study (e.g., a study on the disease/burden of HIV/AIDS)
Research is carried out on publicly available information, documents, records, works, performances, reviews, quality assurance studies, archival materials or third-party interviews, etc.
Research on anonymized biological samples, leftover samples after clinical investigation/research, cell lines, or cell free derivatives (e.g., viral isolates, DNA or RNA from recognized institutions or qualified investigators, samples or data from repositories or registries, etc.) provided permission for future research on these samples has been taken in the previous ICF
In emergency situations when no surrogate consent can be taken
Retrospective studies, where the participants are de-identified or cannot be contacted

Assent Requirements

As delineated in the G-ICMR, the 2019-CTRules, and the G-Children, if the pediatric participant has the capacity for assent, the participant’s affirmative assent is required to participate in a study according to their developmental level and decision-making capacity. Per the 2019-CTRules, mature minors and adolescents should personally sign and date a separately designed written assent form. According to the G-ICMR, mature minors are those from age seven (7) up to age 18.

The G-Children also explains that in addition to the children’s developmental level and capability of understanding, the assent process and form should also take into account their age, maturity, reading level, independence, autonomy as well as cultural and social factors. For children between ages seven (7) and 11, oral assent must be obtained in the presence of their legal representative(s) or guardian(s). For children between ages 12 and 18, written assent must be obtained.

A child’s dissent or refusal to participate must always be respected, and he/she must be informed in an understandable manner that the child may withdraw assent at any time during the study. The EC may also issue a waiver of assent in the following circumstances:

If the research has the potential to directly benefit the child, and this benefit is only available through this study
If the research involves children with intellectual and other developmental disabilities, they may not have the developmental level and intellectual capability to give assent

For details and guidance on preparing and using an assent form, see the G-Children.

First Schedule (3) and Third Schedule (2)

1.5, 2, 3.1-3.3, 4.1, and 6.1

6.5

Pregnant Women, Fetuses & Neonates

Last content review/update: June 16, 2023

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. The following guidance applies to research involving materials related to human reproduction:

Research using materials related to human reproduction in the context of an anticipated or ongoing pregnancy must not be undertaken if the information can reasonably be obtained by alternative methods
Materials related to human reproduction for research use must not be obtained through commercial transaction, including exchange for services

Per the G-TCPS2, research on in vitro embryos already created and intended for implantation to achieve pregnancy is acceptable if:

The research is intended to benefit the embryo
Research interventions will not compromise the care of the woman, or the subsequent fetus
Researchers closely monitor the safety and comfort of the woman and the safety of the embryo
Consent was provided by the gamete donors

According to the G-TCPS2, research involving embryos that have been created for reproductive or other purposes permitted by law, but are no longer required for these purposes, may be ethically acceptable if:

The ova and sperm from which they are formed were obtained in accordance with the G-TCPS2
Consent was provided by the gamete donors
Embryos exposed to manipulations not directed specifically to their ongoing normal development will not be transferred for continuing pregnancy
Research involving embryos will take place only during the first 14 days after their formation by combination of the gametes, excluding any time during which embryonic development has been suspended

Per the G-TCPS2, research involving a fetus or fetal tissue:

Requires the consent of the woman
Must not compromise the woman’s ability to make decisions regarding continuation of her pregnancy

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) and Chapter 12 (Articles 12.6-12.9)

Last content review/update: February 2, 2023

As per the 2019-CTRules and the G-ICMR, clinical studies involving pregnant or nursing women and fetuses require additional safeguards to ensure that the research assesses the risks to the women and the fetuses. The following conditions are required for research to be conducted involving pregnant or nursing women or fetuses.

Per the 2019-CTRules:

Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant or nursing women, fetuses, or nursing infants, and where the data generated from women who are not pregnant or nursing is unsuitable

Per the G-ICMR:

For studies related to pregnancy termination, only pregnant women who undergo Medical Termination of Pregnancy as per the Medical Termination of Pregnancy Act, 1971 can be included
The research should carry no more than minimal risk to the fetus or nursing infant and the research objective is to obtain new knowledge about the fetus, pregnancy, and lactation
Clinical trials involving pregnant or nursing women would be justified to ensure that these women are not deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines, or other agents that promise therapeutic or preventive benefits
Research related to prenatal diagnostic techniques in pregnant women should be limited to detecting fetal abnormalities or genetic disorders as per the Pre-Conception and Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, 1994, amended in 2003, and not used to determine the sex of the fetus
Researchers must provide the ethics committee (EC) with proper justification for including pregnant and nursing women in trials designed to address the health needs of such women or their fetuses or nursing infants
If women of reproductive age are to be recruited, they should be informed of the potential risk to the fetus if they become pregnant, be asked to use an effective contraceptive method, and be told about the options available in case of failure of contraception
A woman who becomes pregnant must not automatically be removed from the study when there is no evidence showing potential harm to the fetus. The matter should be carefully reviewed, and she must be offered the option to withdraw or continue
If the female sexual partner of a male participant gets pregnant during his research participation, the EC should review the protocol and informed consent form (ICF) to determine if a plan exists to document this event, and both the pregnant partner and fetus must also be followed for the outcome and reported in the study results
Pregnant women have the right to participate in clinical research relevant to their healthcare needs (e.g., gestational diabetes, pregnancy-induced hypertension, and HIV)
Benefit-risk assessment must be done at all stages for both the mother and the fetus
Research involving pregnant women and fetuses must only take place when the objective is to obtain new knowledge directly relevant to the fetus, the pregnancy, or lactation
Women should not be encouraged to discontinue nursing for the sake of participation in research except in those studies where breastfeeding is harmful to the infant
Appropriate studies on animals and non-pregnant individuals should have been completed, if applicable
Researchers should not participate in decision-making regarding any termination of a pregnancy
No procedural changes, which will cause greater than minimal risk to the woman or fetus, will be introduced into the procedure for terminating the pregnancy solely in the interest of the trial
When research is planned on sensitive topics (e.g., domestic violence, genetic disorders, and/or rape) confidentiality should be strictly maintained and privacy protected

Fetuses and Neonates

As described in the G-Children, study protocols involving neonates should take into consideration that this group is the most vulnerable within the pediatric population in terms of the risk of long-term effects of interventions, including developmental effects. ECs reviewing such proposed protocols should have an advisory member with expertise in neonatal research/care. ECs should scrutinize all proposed research for potential risks and weigh them against the possible benefits and ensure a competent person(s) conducts a proper scientific review of the protocol. In addition, when possible, older children should be studied before conducting studies in younger children and infants.

The consent of one (1) parent is also required for neonate studies where research exposes them to no or minimal risk, or in studies that offer the prospect of direct benefit to the participant. However, for studies that do not offer the prospect of direct benefit or are high-risk, consent from both parents is required. Exceptions to this requirement include the following:

Only one (1) parent has legal responsibility for the care and custody of the child
One (1) parent is deceased, unknown, incompetent, or not available. In such cases, it is the duty of the investigators to provide adequate justification.

If one (1) of the parents is a minor, then he/she should not provide consent. If both parents are minors, then enrollment of such a baby should be avoided as much as possible. Investigator(s) should provide adequate justification to the EC to enroll such neonates for research. A legally acceptable representative should provide an informed consent in such situations.

First Schedule (3)

6.1

6.4 and 7.18

Prisoners

Last content review/update: June 16, 2023

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 2, 2023

As noted in the G-ICMR, prisoners are included in the description of vulnerable populations due to their diminished autonomy caused by dependency or being under a hierarchical system.

The G-ICMR specifies that during the review process, the ethics committee (EC) must ensure compliance with the following:

Enrolling participants is specifically pertinent to the research questions and is not merely a matter of convenience
Extra efforts are made to respect the autonomy of these individuals because they are in a hierarchical position and may not be in a position to disagree to participate for fear of authority
It is possible for the participant to deny consent and/or later withdraw from the study without any negative repercussions on her/his care
Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol

6.9

Mentally Impaired

Last content review/update: June 16, 2023

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).

Per CAN-35, 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

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.

Consent Process (Key Considerations)

1.61 and 3.1

Chapter 3 (Article 3.7-3.10)

Last content review/update: February 2, 2023

The G-ICMR states that, in the case of differently abled participants, such as those with physical, neurological, or mental disabilities, appropriate methods should be used to enhance the participants’ understanding. The G-ICMR also states that the presence of a mental disorder is not synonymous with incapacity of understanding or inability to provide informed consent. However, ethics committees (ECs) have special responsibilities when research is conducted on participants who are suffering from mental illness and/or cognitive impairment. ECs should exercise caution and require researchers to justify exceptions and their need to depart from the guidelines governing research. ECs should ensure that these exceptions are as minimal as possible and are clearly spelled out in the informed consent form. The G-ICMR also upholds the Declaration of Helsinki (IND-63).

As set forth in the MHA2017, every person, including a person with mental illness, must be deemed to have the capacity to make decisions regarding mental healthcare or treatment providing the person has the ability to engage in the following:

Understand the information that is relevant to make a decision on treatment, admission, or personal assistance
Appreciate any reasonably foreseeable consequence of a decision or lack of decision on the treatment, admission, or personal assistance, or
Communicate the decision by means of speech, expression, gesture, or any other means

Per MHA2017, information must be provided to a person with mental illness using simple and understandable language, sign language, visual aids, or any other means to enable the person to understand the information. In the case in which a person makes a decision regarding one’s mental healthcare or treatment that is perceived by others as inappropriate or wrong, that by itself, must not be interpreted as the person not having the capacity to make such a decision, as long as the person has the capacity to meet the above stated requirements.

MHA2017 further delineates that every person with mental illness who is not a minor must have the right to appoint a nominated representative. The nomination must be made in writing on plain paper with the person’s signature or thumb impression. The person appointed as nominated representative must not be a minor, be competent to discharge the duties or perform the assigned functions under the MHA2017, and give consent in writing to the mental health professional to discharge the person’s duties and perform the assigned functions. A person who has appointed an individual as the nominated representative may revoke or alter the appointment at any time. The appointment of a nominated representative, or the inability of a person with mental illness to appoint a nominated representative, must not be construed as the lack of capacity of the person to make decisions about mental healthcare or treatment. All persons with mental illness must have the capacity to make mental healthcare or treatment decisions but may require varying levels of support from their nominated representative to make decisions. When fulfilling responsibilities, the nominated representative must have the right to give or withhold consent for research under circumstances.

Pursuant to MHA2017, professionals conducting research must obtain free and informed consent from all persons with mental illness for participation in any research that involves interviewing the person, or any research that involves psychological, physical, chemical, or medicinal interventions. In the case of research involving psychological, physical, chemical, or medicinal interventions to be conducted on a person who is unable to give free and informed consent, but does not resist participation in such research, permission to conduct such research must be obtained from the concerned State Authority. The State Authority may allow the research to proceed based on informed consent being obtained from the person’s nominated representative if the State Authority is satisfied that the following criteria are met:

The proposed research cannot be performed on persons who are capable of giving free and informed consent
The proposed research is necessary to promote the mental health of the population represented by the person
The purpose of the proposed research is to obtain knowledge relevant to the particular mental health needs of persons with mental illness
A full disclosure of the interests of the persons and organisations conducting the proposed research is made and there is no conflict of interest involved, and,
The proposed research follows all the national and international guidelines and regulations concerning the conduct of such research, and ethical approval has been obtained from the institutional EC where such research is to be conducted

A research-based study of the case notes of a person who is unable to give informed consent will be permitted so long as the anonymity of the person is secured. In addition, the person with mental illness or the nominated representative who gives informed consent for participation in any research under MHA2017 may withdraw consent at any time during the research period.

5.3-5.4, 6.3, 6.5, and 6.8

Chapter I (Section 4), Chapter IV (Sections 14 and 17), and Chapter XI (Section 99)

Definition of Investigational Product

Last content review/update: June 16, 2023

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.

3.0

1.33

5.1

Part C (Division 5 (C.05.001))

Last content review/update: February 2, 2023

As delineated in the 2019-CTRules, an investigational product (IP) is defined as the pharmaceutical formulation of an active ingredient or a placebo (including the comparator product) being tested or used as a reference in a clinical trial.

The 2019-CTRules further defines an investigational new drug as a new chemical or biological entity or a product having a therapeutic indication, but which has never been tested before on human participants.

Chapter I (2)

Manufacturing & Import

Last content review/update: June 16, 2023

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 authorizes 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 authorization template (Appendix 1) in 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 the authorization template in CAN-4 should be provided to HC. The G-FDR-0100, provides additional guidance on requirements if a sponsor plans to send the clinical trial IP(s) directly to each trial site:

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).

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, 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) must be included 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 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 interpretations of the relevant provisions of the CanadaFDR.

Appendix 1

Drug Importation

1.0

2.12 and 5.13

2.3 and 2.7

5.2-5.3 and 5.6

I, S Drug Substance, and P Drug Product

Section # Block D and Appendix 1 Guidance

Importer’s Role, Table 1, and Human Drugs

Part C (Divisions 2-5)

Last content review/update: February 2, 2023

Manufacturing

As specified in the 2019-CTRules and IND-31, the Drugs Controller General of India (DCGI) is responsible for authorizing the manufacture of investigational products (IPs) in India. The DCGI approves the manufacture of IPs as part of the clinical trial application review and approval process. The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.

The 2019-CTRules explains that applicants must apply to the DCGI using Form CT-10 to obtain permission to manufacture an IP for clinical trial purposes. After reviewing Form CT-10 and any supplemental information, the DCGI will either grant permission to manufacture the IP via Form CT-11 or reject the application, for reasons to be recorded in writing, within 90 working days from the date of application receipt. If applicable, the DCGI must inform the applicant of deficiencies in the application within 90 working days. If the applicant chooses to rectify the deficiencies within the specified period and provide the required information and documents, the DCGI must review the application again. Based on the review, the DCGI will either grant manufacturing permission to the applicant or reject the application within a period of 90 working days from the date the required information and documents were provided. In the case of rejection, the applicant may request the DCGI reconsider the application within a period of 60 working days from the rejection date along with payment of the specified fees in the 2019-CTRules and submission of the required information and documents. Refer to the 2019-CTRules for additional timeline information and the applicable forms.

Applicants who intend to manufacture an unapproved active pharmaceutical ingredient (API) to develop a pharmaceutical formulation for clinical trial purposes should submit to the DCGI either Form CT-12, if applying as a pharmaceutical formulation manufacturer, or Form CT-13, if applying as an API manufacturer, and any supplemental information. After reviewing the submission and conducting further inquiry, if needed, the DCGI will grant permission to the applicant to manufacture the unapproved API in Form CT-15 and permission to the manufacturer of the pharmaceutical formulation in Form CT-14 within 90 working days. If dissatisfied, the DCGI will reject the application, for reasons to be recorded in writing, within a period of 90 working days from the application submission date. Refer to the 2019-CTRules for additional timeline information and the applicable forms.

In addition, Notice18Feb20 clarifies information provided in IND-31 concerning where applications should be sent to obtain permission to manufacture trial batches of new drugs or IPs for testing and analysis, clinical trials, or bioavailability and bioequivalence (BA/BE) studies. For biological drugs, applications should be sent to CDSCO Headquarters (HQ) at FDA Bhavan, New Delhi; for drugs other than biologicals, applications should be sent to the appropriate zonal office/sub-zonal office for pure chemical testing, and the zonal office/sub-zonal office or CDSCO HQ for clinical trials or BA/BE studies. Furthermore, if the applicant obtains permission to manufacture new drugs/IPs for a clinical trial or BA/BE study, he/she should automatically consider the approval as permission to conduct other chemical/physical testing and analysis on these new drugs/IPs. Refer to IND-58 for detailed CDSCO HQ, zonal office/sub-zonal office contact information. Notice20Feb20 further specifies that applications sent to either CDSCO HQ or the appropriate zonal office/sub-zonal office will be processed within seven (7) working days of receipt.

Notice18Feb20 states that applicants must clearly mention the site where the product will be manufactured in their applications using the following statement: M/s. [name and address of the firm] having manufacturing premises for test and analysis at [name and address of the manufacturing site for test and analysis]. Refer to Notice18Feb20 for additional information.

Per Notice13Mar20, when the application is solely to conduct a clinical trial, the DCGI also requires the sponsor (also known as applicant) to submit the international non-proprietary name (INN) or generic name, drug category, dosage form, and data supporting IP stability in the intended container-closure system for the duration of the clinical trial. See the 2019-CTRules (Second Schedule, Table 1) for detailed data requirements. Additionally, for Phase III clinical trial batches, process validation data requirements may not be required; however, this requirement will vary depending on the IP’s complexity (biological, high tech, etc.).

If approved, the DCGI will grant permission for a period of three (3) years to both manufacturers of new drugs or investigational new drugs and manufacturers of unapproved APIs. In exceptional circumstances, the DCGI may extend the period of permission for an additional year. See the 2019-CTRules and IND-31 for more detailed information on manufacturing application submission requirements.

Import

As delineated in the 2019-CTRules and IND-31, the DCGI is responsible for authorizing the import of IPs in India. The DCGI approves the import of IPs as part of the clinical trial application review and approval process.

Per the 2019-CTRules and IND-31, the sponsor is required to obtain a license from the DCGI using Form CT-16 to import an IP (new drug or investigational new drug) for clinical trial purposes. Per the 2019-CTRules, the sponsor must also ensure that the imported IPs are manufactured in accordance with Good Manufacturing Practices (GMPs) as laid down in the DCA-DCR. Refer to Schedule M of the DCA-DCR to review the GMP requirements. See also the Second Schedule in the 2019-CTRules for the data requirements to be included in the DCGI’s import application.

The 2019-CTRules and IND-31 further state that the DCGI will grant an import license within 90 working days of receipt of the application. Once approved, the import license must remain valid for three (3) years from the date of issue, unless suspended or cancelled. In exceptional circumstances, the DCGI may extend the license for an additional year. (See the Submission Process, Submission Content, and Regulatory Fees sections for detailed clinical trial application requirements). See also IND-35 for a checklist of manufacturing and import related forms to be included in a global clinical trial application submission. According to the 2019-CTRules, the sponsor must submit a fee of 5,000 Indian National Rupees (INRs) per product with an application for permission to manufacture or import the IP to be used in a clinical trial. Refer to IND-43 and IND-42 for detailed fee requirements and online payment instructions via the SUGAM portal (IND-59).

As explained in IND-25, the DCGI does not require a drug import license to be obtained when an ethics committee (EC) has granted approval for the conduct of an academic clinical trial that will be using a permitted drug formulation with a new indication, a new route of administration, a new dose, or a new dosage form. A copy of the EC approval for the trial must be provided to the Port office at the time of import along with a letter of undertaking that specifies the quantity of the drug being imported and states that it will be used exclusively for the academic clinical trial.

In addition, per the 2019-CTRules and IND-31, the DCGI will relax, abbreviate, omit, or defer clinical and non-clinical data requirements to import or manufacture new drugs already approved in other countries on a case-by-case basis for life threatening or serious/rare diseases and drugs intended to treat diseases of special relevance to the Indian population, unmet medical needs in India, and in disaster or special defense use (e.g., hemostatic and quick wound healing, enhancing oxygen carrying capacity, radiation safety, or drugs to combat chemical, nuclear, or biological conditions). This decision will vary depending on the specific clinical trial phase proposed and the clinical parameters related to the study drug.

Please note: India is party to the Nagoya Protocol on Access and Benefit-sharing (IND-29), 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 IND-45.

64-67, 71-75, and 79

1.6

1, 4, and 6

Foreword, Step 1, Step 2, and Step 5

DCR, 1945 - Schedule M

65 and 123

Chapter V (25), Chapter VIII (52-54, 59-61, and 64), Chapter IX (67-70), Chapter X (75), Chapter XIII (101), Second Schedule (1 and Table 1), Sixth Schedule, Eighth Schedule (Forms CT-10, CT-11, CT-12, CT-13, CT-14, CT-15, and CT-16)

Quality Requirements

Last content review/update: June 16, 2023

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.

Quality Management

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.

4

2.12, 5.13, 7.3, and 8.2

4

2.8

5.1, 5.5, and 5.12

Part C (Division 5 (C.05.001, C.05.005, and C.05.012))

Last content review/update: February 2, 2023

Investigator's Brochure

The 2019-CTRules requires the Investigator’s Brochure (IB) to contain the version number, release date, and the following sections:

Contents
Summary
Introduction
Physical, Chemical, and Pharmaceutical Properties and Formulation
Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
Effects in humans (Pharmacokinetics and Product Metabolism in Humans, Safety and Efficacy, and Marketing Experience)
Summary of Data and Guidance for the Investigator

Refer to the 2019-CTRules for detailed content guidelines.

Per the 2019-CTRules, the licensee is responsible for ensuring the products are manufactured in accordance with the principles of Good Manufacturing Practice (GMP). (See the Product Management section for additional information on investigational product (IP) supply, storage, and handling requirements).

Additionally, per Notice13Mar20, when the application is solely to conduct a clinical trial, the DCGI also requires the sponsor (also known as applicant) to submit the international non-proprietary name (INN) or generic name, drug category, dosage form and data supporting IP stability in the intended container-closure system for the duration of the clinical trial (see the Second Schedule, Table 1 in the 2019-CTRules for detailed data requirements). Additionally, for Phase III clinical trial batches, process validation data requirements may not be required; however, this requirement will vary depending on the IP’s complexity (biological, high tech, etc.).

Quality Documentation

As noted in the 2019-CTRules the applicant is required to provide the following:

A free sale certificate from country of origin
Certificate(s) of analysis of IP shipped

Per IND-75, the Central Drugs Standard Control Organization (CDSCO) determined that the Certificate of Pharmaceutical Product (COPP) should be issued under the World Health Organization (WHO) GMP Certification Scheme and extended the validation period from two (2) to three (3) years subject to the condition that the manufacturing facility GMP status be monitored per WHO guidelines through periodic inspections.

Further, per the 2019-CTRules, the submission of requirements related to pre-clinical/toxicological animal studies may be modified or relaxed in the case of new drugs approved or marketed for several years in other countries if the DCGI determines there is adequate published evidence regarding a drug’s safety.

See IND-35 for a checklist of global clinical trial (GCT) documentation requirements.

1

Chapter VIII (55 and 63), Chapter IX (70), Chapter X (75), Chapter XIII (101), Second Schedule (Table 1), Third Schedule (Table 7), and Eighth Schedule (Forms CT-10, CT-12, and CT-16)

Labeling

Last content review/update: June 16, 2023

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.

In addition, the CA-ICH-GCPs state that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

8.7

5.13

2.8.7

5.11

Part C (Divisions 2 (C.02.006, C.02.011, C.02.015-016) and 5 (C.05.011))

Last content review/update: February 2, 2023

Per the 2019-CTRules and IND-31, the labeling of any new drug or investigational new drug product manufactured or imported for the purpose of conducting a clinical trial or for testing and analysis should include the following items:

The drug name or code number
Batch number or lot number
Manufacture date
Use before date
Storage conditions
Name of institution/organization/center where the clinical trial or testing and analysis is proposed to be conducted
Manufacturer name and address
Purpose for which the investigational product is being imported

Chapter VIII (66) and Chapter IX (73)

70

Product Management

Last content review/update: June 16, 2023

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 investigational products (IP(s)), including the comparator and placebo, if applicable. The sponsor should not supply the IP(s) until approvals from Health Canada (HC) and the institutional ethics committee (EC) are obtained. 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

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 packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage. Refer to the CA-ICH-GCPs for detailed sponsor-related IP requirements.

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.

8.6

5.5, 5.12, 5.13, 5.14, and 7

5.1, 5.5, 5.10, and 5.12

Part C (Division 5 (C.05.001, C.05.005, C.05.010, and C.05.012))

Regulatory Impact Analysis Statement

Last content review/update: February 2, 2023

Supply, Storage, and Handling Requirements

According to the 2019-CTRules and IND-31, in the event that a new drug or investigational new drug manufactured for clinical trial or testing and analysis purposes is left over, remains unused, incurs damage, has an expired shelf life date, or has been found to be of sub-standard quality, the drug must be destroyed and the action taken should be recorded.

Per the 2019-CTRules, the investigational product (IP) section of the protocol submitted as part of the clinical trial application must include the following:

IP description and packaging (i.e., IP ingredients and formulation, and placebos used, if applicable)
Dosing required during study
Packaging, labeling, and blinding method
Method of assigning treatments to participants and identification code numbering system to be used
Storage conditions
Accountability (e.g., instructions for receipt, storage, dispensation, and return of IPs)
Policy and procedure for handling unused IPs

Record Requirements

No information is currently available on IP record requirements.

Chapter VIII (55) and Third Schedule (Tables 2 and 7)

68

Definition of Specimen

Last content review/update: June 16, 2023

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).

Glossary

Chapter 12 and Glossary

Last content review/update: February 2, 2023

In India, per the G-XBiolMat, the G-ICMR, and the G-StemCellRes, a specimen is referred to as “human biological material,” “human biological sample,” “biological material,” or “biospecimen.” The G-XBiolMat defines a specimen as human material with the potential for use in biomedical research. According to the G-XBiolMat, the G-ICMR, and the G-StemCellRes, this material specifically includes (Note: The regulatory sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

Organs and parts of organs
Cells and tissue
Blood (e.g., cord blood and dried blood spots)
Gametes (e.g., sperm, ova, and oocytes)
Embryos and fetal tissue
Blastocysts
Somatic cells

The G-XBiolMat definition also includes the following:

Sub-cellular structures and cell products
Wastes (e.g., urine, feces, sweat, hair, epithelial scales, nail clippings, placenta, etc.)
Cell lines from human tissues

As per the G-XBiolMat, these biological specimens or human material samples may be obtained from the following sources:

Patients following diagnostic or therapeutic procedures (e.g., dental, labor, etc.)
Autopsy specimens
Organ or tissue donation from living or dead persons
Fetal tissue
Body waste
Abandoned tissue
Tissue banks

Chapter III, Review Procedures, Section 3

15.0

Definition

Specimen Import & Export

Last content review/update: June 16, 2023

Import/Export

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.

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. Per CAN-2, 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. 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.

Chapter 21

Chapters 1 and 2

Blood and blood components for transfusion

Purpose of the Act, Interpretation and Application, Obligation, Prohibitions, and Licenses

Licenses

Last content review/update: February 2, 2023

Import/Export

As specified in the G-XBiolMat, the HumBiol-ImprtExprt, and IND-55, the applicable import/export guidelines for human biological materials/specimens in India are determined by whether the materials are to be used for biomedical research or for commercial purposes. According to IND-55, the G-XBiolMat should be followed to import/export human biological material for biomedical research purposes, and the HumBiol-ImprtExprt is to be used to import/export human biological samples for commercial purposes.

Biomedical Research

According to the G-XBiolMat, the following guidelines should be considered for requests to transfer biological material abroad for research/diagnostic purposes, and for requests to transfer biological material from abroad to Indian institutions for research purposes:

Exchange of material for diagnostic or therapeutic purposes for individual cases may be done without restriction, if this exchange is considered necessary by the doctor(s) in charge of the patient
Exchange of material from and to recognized laboratories such as the World Health Organization (WHO)’s Collaborating Centres may be allowed as part of routine activities relating to quality control, quality assurance, comparison with reference material, etc., without having to seek permission from any authority
Where exchange of material is envisioned as part of a collaborative research project, the project proposal as a whole must be routed through the appropriate authorities for evaluation and clearance (see International Research Collaboration section below for additional information)
The availability of facilities within India for carrying out certain investigations need not prevent collaboration with scientists in other countries from conducting the same investigations, including transfer of human material, if required
For the technology transfer/training of Indian scientists abroad/training of foreign scientists and students in India, and visits by foreign collaborators to their Indian partners’ laboratories to work with Indian material, there should be no restrictions on the visits of scientists to the laboratories concerned. However, any fieldwork to be undertaken in the community and other sensitive issues would have to be regulated according to the National Portal of India’s rules

International Research Collaboration

In the case of international research collaboration involving human biological material transfer, the G-XBiolMat and the G-ICMR indicate that the export of all biological materials is to be covered under existing Government of India and ethics guidelines. The G-ICMR further specifies that all biomedical and health research proposals relating to foreign assistance and/or collaboration should be submitted to the Indian Council of Medical Research (ICMR) for a technical review. Next, the ICMR submits the project to the Health Ministry’s Screening Committee (HMSC) for review and approval through its International Health Division that serves as the HMSC’s secretariat. Refer to IND-15 for detailed information on the HMSC.

Per the G-ICMR, the ethics committee (EC) may review research proposals requiring biological material transfer on a case-by-case basis. The exchange of human biological material from and to WHO Collaborating Centres for specific purposes, as well as for individual cases of diagnosis or therapeutic purposes, may not require permission. However, Indian participating center(s) must have appropriate regulatory approval and registration to receive foreign funds for research.

See IND-1 for the application form to request a no objection certificate (NOC) to export biological samples. Refer to the G-XBiolMat, the G-ICMR, IND-74, and IND-27 for additional information.

Commercial Purposes

According to the HumBiol-ImprtExprt, per the Directorate General of Foreign Trade (DGFT) within India’s Ministry of Commerce and Industry, the import of human biological samples by Indian diagnostic laboratories/Indian clinical research centers for laboratory analysis/research and development testing, or, for exporting these materials to foreign laboratories, should be permitted by customs authorities at the port of entry/exit without prior approvals (import license/export permit) from any other government agency. In these cases, the concerned Indian company/agency should submit a statement that it is following all the applicable rules, regulations, and procedures for the safe transfer and disposal of biological samples being imported/exported. For more information, see the HumBiol-ImprtExprt.

Material Transfer Agreement

Per the G-ICMR and IND-74, any research involving the exchange of biological materials with collaborative institutions outside India must sign a Material Transfer Agreement (MTA). The MTA must justify the purpose and quantity of the sample being collected; the type of investigation(s) to be conducted using the material; the names/addresses of institution(s)/scientist(s) to whom the material is to be sent; and address confidentiality issues, data sharing, post-analysis handling of remaining biological materials, safety norms, etc. The G-ICMR also indicates that an appropriate memoranda of understanding (MoU) should be in place to safeguard mutual country interests and ensure compliance.

Per the G-XBiolMat, the collaborating partners (India and foreign) should enter into an MoU and/or MTA for requests to transfer biological material abroad for research/diagnostic purposes, and for requests to transfer biological material from abroad to Indian institutions for research purposes.

3.8 and 11.4

Definition, Transfer, Mechanism, and Exchange of Biological Material for Commercial Purposes

Section 11

Some Important points for Consideration by PIs

Consent for Specimen