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Research Ethics Board's Operational Policy Framework: Health Canada and Public Health Agency of Canada

Ethics review of research involving human subjects.

Issued by: REB Secretariat Approved by:   Research Ethics Board Date 1 st issued: April 1, 2010

On this page

• About this Policy Framework
• Authorities 2.1 Empowering Authority 2.2 Appointment of Members 2.3 Decisional Authority  
• Mandate and Scope 3.1 Mandate of the REB   3.1.1 Definition of Research   3.1.2 Definition of Human Subjects 3.2 Scope of the REB   3.3 Situations Where REB Review May be Required 3.3.1 General   3.3.2 Surveillance 3.3.3 Supplemental Services 3.3.4 Quality Assurance 3.3.5 Analysis of Publicly Available Data
• Membership 4.1 Full Membership 4.2 Alternate Membership 4.3 Appointment  
• Roles and Responsibilities 5.1 Decisional Authority 5.2 REB Chair 5.3 REB Members/Alternate Members 5.4 REB Secretariat   5.5 Confidentiality 5.6 Conflict of Interest of REB Members 5.7 Policy on Indemnification  
• Meeting Requirements
• Types of REB Review   7.1 Full Reviews   7.2 Expedited Reviews 7.3 Time Sensitive Reviews  
• Elements of the REB Review 8.1 Scientific Design and Conduct of the Study 8.2 Recruitment of Research Subjects 8.3 Care and Protection of Research Subjects  8.4 Protection of Research Subject's Confidentiality 8.5 Informed Consent Process 8.6 Community Considerations
• REB Ethics Recommendations
• REB Reconsideration and Appeals 10.1 Reconsideration of a Negative Ethics Recommendation 10.2 Appeal of a Negative Ethics Recommendation following Reconsideration
• Continuing Ethics Review   
• Annual Report
• Documentation and Archiving

Download the alternative format (PDF format, 120 KB, 21 pages)

Organization: Health Canada

Type: Report

Date published: 2016-04-01

Related Topics

• Health science and research
• Panel on Research Ethics

1. About This Policy Framework

This Operational Policy Framework of the Research Ethics Board (REB) was approved by the Deputy Minister (DM) of Health and the Chief Public Health Officer (CPHO) of the Public Health Agency of Canada (PHAC) in 2010.  However, since research ethics is a continually evolving subject matter, this Policy Framework may be modified from time to time.  It is the responsibility of all researchers and other readers to ensure that they are using the most recent version.  The Policy Framework should be read in conjunction with the REB's Administrative Procedures Manual which provides important information on the procedures adopted by the REB for reviewing research applications.

2. Authorities

In April 2006, Health Canada and PHAC entered into a Memorandum of Understanding that gave Health Canada's REB the mandate to conduct ethics reviews of PHAC research projects involving human subjects. 

In the Fall of 2009, an agreement was reached between officials from Health Canada and PHAC for the establishment of a joint REB.  On April 1, 2010, the REB will become fully operational as a joint REB for both institutions.   The REB Secretariat will be responsible for managing and communicating with the REB members on all research protocols received for ethics review from both institutions.

2.1 Empowering Authority

The REB derives its legitimacy from authority delegated by the DM and CPHO.  For the sake of transparency, the following information shall be kept public at all times:  the REB's terms of reference, membership, policy framework and administrative procedures.

2.2 Appointment of Members

The DM and CPHO will jointly appoint all REB members and alternate members to the REB, including the Chair. 

2.3 Decisional Authority

The DM and CPHO may delegate their decisional authority functions to a senior official within Health Canada and PHAC respectively, each of whom will be referred to as the “Decisional Authority in Research Ethics” (hereinafter Decisional Authority).

3. Mandate and Scope

3.1 mandate of the reb.

The REB shall serve as an independent Board to help ensure that all proposed or ongoing research involving human subjects carried out by, funded by, or otherwise under the auspices of Health Canada or PHAC, meets the highest ethical standards, and that safeguards are implemented to provide the greatest protection to human subjects. It will make recommendations as to whether research projects should be approved, rejected, modified, or terminated.  The REB shall review applications in accordance with the considerations set forth in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans Footnote 1 ( TCPS ) as the minimum standard.

3.1.1    Definition of Research

For the purposes of this REB, research shall be defined as an activity designed to test a hypothesis, permit conclusions to be drawn and develop or contribute to generalizable knowledge, using scientific methods and standardized protocols. Generalizable knowledge consists of theories, principles or relationships, or the accumulation of information on which they are based, that can be corroborated by accepted scientific methods of observation and inference. In the present context “research” includes both medical and behavioural studies pertaining to human health.

3.1.2    Definition of Human Subjects

The involvement of human subjects is required where progress in medical care and disease prevention depends upon an understanding of physiological and pathological processes or epidemiological findings. The collection, analysis and interpretation of information obtained from research involving human subjects contribute significantly to the improvement of human health. Research involving humans as “research subjects” includes research with

• Living individuals;
• Human remains, cadavers, embryos or foetuses;
• Human biological materials such as tissues, organs, blood, plasma, serum, DNA, RNA, proteins, cells, hair, nail clippings, faeces, urine, saliva and other body fluids; and
• Information from or about humans, such as information obtained through surveys, and from records of nonliving humans that are not in the public domain.

3.2 Scope of the REB

The REB shall review all research involving human subjects as defined above in circumstances where the research is:

• Carried out by Health Canada or PHAC employees in the course of their employment;
• Carried out on Health Canada or PHAC premises, or involves technical or consultation support including the use of equipment, laboratories or other facilities belonging to HC or PHAC;
• Undertaken in a collaboration or partnership between Health Canada or PHAC and external researchers;
• Funded internally or externally through Health Canada or PHAC grants and contributions; or  
• Carried out under contract with Health Canada or PHAC.

Further, such research is subject to REB review whether:

• The funding is internal or external;
• The research is conducted inside or outside Canada;
• The subjects are compensated or not;
• The research is conducted by staff or by students;
• The research is conducted in person, remotely (e.g. by mail, electronic mail, fax or telephone) or uses previously collected data/samples and requires no direct contact with subjects;
• The research is to be published or not;
• The research is observational, experimental, correlational or descriptive;
• The research has been reviewed by another REB;
• The research is a pilot study or a fully developed project;
• The research aims to develop basic or applied knowledge; or
• The research is primarily for teaching or training purposes.

3.3 Situations Where REB Review May be Required

3.3.1 general.

Some boundaries between research and non-research activities may be difficult to define.  As a general rule, whenever there is uncertainty as to whether a proposed activity requires REB review (as in the situations outlined below or otherwise), the following offices should be consulted:

• For Health Canada: the REB Secretariat;
• For PHAC: the Public Health Law and Ethics Program.

3.3.2 Surveillance

Surveillance is often defined as the systematic ongoing collection, analysis and interpretation of health data that is essential to the planning, implementation, and evaluation of public health practice and closely integrated with the timely dissemination of the data to those who need to know. The final link in the surveillance chain is the application of the data to disease prevention and control.  A surveillance system includes a functional capacity for data collection, analysis and dissemination linked to public health programs.  Not all surveillance activities may require an ethics review by the HC and PHAC REB. However, since this determination can only be made on a case-by-case basis, the advice of the REB should be sought.

3.3.3  Supplemental Services

Health Canada and PHAC officers often receive requests to provide analytical services for research projects led by external research teams.  For example a Health Canada or PHAC scientist may be asked to analyze anonymous or anonymized human biological material samples without engaging in their collection. Normally, requests for such supplemental services will require a REB review.  However, the component of the project to be undertaken by Health Canada or PHAC may not require an ethics review/approval by the REB in instances where the following three conditions are met:

• The officer’s activities in the project consist solely of performing an analytical service;
• Health Canada and/or PHAC is not involved in the collection of the data or biological material; and
• Health Canada and/or PHAC do not plan to be acknowledged or be a partner/co-author in the publications resulting from the project.

In all instances, however, the REB Secretariat or the Public Health Law and Ethics Program should be consulted in all instances.

3.3.4 Quality Assurance

Quality assurance is a system that aims to:

• Evaluate and review the quality of a program, service, or a product within a particular institution;
• Identify problems or deficiencies in design or delivery;
• Design activities and procedures to overcome these deficiencies; and
• Monitor the effectiveness of corrective measures.

If the project has any element of research (for example, if it uses a novel approach) an ethics review shall be required by the REB.  However, quality assurance that is conducted in a routine or usual manner does not require REB review so long as the following three conditions are met:

• It is intended solely for internal use within an individual institution;
• It only measures the integrity of the functions delivered by the organization or performance of staff internal to the institution while carrying out their duties and responsibilities; and
• It is not intended to contribute to generalizable scientific knowledge about treatments and procedures by being published.

3.3.5    Analysis of Publicly Available Data

REB review is generally not required for research involving public policy issues even though these might well involve human subjects.

4. Membership

4.1 full membership.

The REB will consist of at least nine members. These include the Chair and a Deputy Chair to be named by the Chair.

The REB membership shall include:

• At least three members with broad expertise in the methods of Health Canada or PHAC research: one from outside Health Canada and PHAC, one from Health Canada, and one from PHAC;
• At least two members who are knowledgeable in ethics;
• At least one member who has broad expertise in public health;
• At least one member who is knowledgeable in the relevant law; and
• At least two members who have no affiliation with Health Canada or PHAC, one recruited from the community served by Health Canada and PHAC, and another recruited from the Aboriginal community.

These membership requirements are designed to ensure that the REB has the expertise, independence and multidisciplinary background essential for competent research ethics review. The REB should also reflect gender and official language dualities as well as Canada's geographical and ethnic diversity.

Although the REB community representatives may have some knowledge of human subject research as members of the public, their role is to bring a different perspective from that of individuals who work in the field of human research.

4.2 Alternate Membership

Article 1.3 of the TCPS provides that institutions should also consider the nomination of substitute REB members so that Boards are not paralysed by illness among its members or other unforeseen events. The use of alternate members should not, however, alter the membership structure as outlined in this section and in the TCPS.

Alternate membership of the REB shall consist of:

• Three members with broad expertise in the methods of research conducted by Health Canada/PHAC: one from outside Health Canada/PHAC, one from Health Canada, and one from PHAC;
• One member who is knowledgeable in ethics;
• One member who has broad expertise in public health;
• One member who is knowledgeable in the relevant law; and
• Two members who have no affiliation with Health Canada/PHAC, one recruited from the community served by Health Canada/PHAC, and another recruited from the Aboriginal community.

Alternate members shall be invited to REB meetings on a rotational basis. They may participate in the discussion of the research application but may not participate in the final decision of the Board. When a REB member is unable to attend a meeting and an alternate member attends in that member's place, the alternate member may participate fully in the decision-making of the Board.

4.3 Appointment

REB members, alternate members and the REB Chair are appointed by the DM and the CPHO for a three-year term. Their terms of membership may be renewed to ensure the continued availability of qualified members on the REB.

The REB Secretariat shall provide to the REB members and alternate members an orientation guide to Health Canada and PHAC, a description of the responsibilities of the REB, and ongoing training.

5. Roles and Responsibilities

5.1 decisional authority.

The Decisional Authority of Health Canada or PHAC shall be responsible for the implementation of Health Canada or PHAC's research ethics policy, respectively, and shall have the following responsibilities in particular:

• Directing, in writing, that researchers must submit their proposals to the REB if they have not done so;
• Conveying, in writing, the REB recommendations and his or her decisions to the Principal Investigator (PI);
• Directing, in writing, that the research be suspended if it has not received an ethics review or if there is reason to believe it is proceeding contrary to the recommendations of the REB;
• Promptly advising the DM or CPHO, as the case may be, of serious adverse events, and the suspension or termination of an approved research project, as recommended by the REB, providing a statement of the reasons for the action taken; and
• Reporting annually to the DM/CPHO on the REB's activities and recommendations.

5.2 REB Chair

The REB Chair shall be responsible for the overall management of the REB and its ethics review process. The duties of the Chair shall include:

• Chairing the meetings;
• Determining if proposals are suitable for expedited review;
• Reaching a decision on whether to recommend that the Decisional Authority allow the proposed research to proceed on ethical grounds;
• Conveying, in writing, the REB ethics recommendations to the Decisional Authority;
• Speaking on behalf of the REB;
• Developing guidelines and procedures for implementing the requirements of this policy consistent with the needs of the relevant research disciplines served by the REB;
• Monitoring the REB's recommendations for consistency and ensuring that these recommendations are recorded properly;
• Promptly reporting any adverse events and recommended suspension or termination of a research project to the Decisional Authority and other institutional officials as deemed appropriate by the REB, and providing a statement of the reasons for the action taken;
• Providing an Annual Report on REB activities to the Decisional Authority; and
• Performing all of the duties of a REB member as outlined in the subsection below.

5.3 REB Members/Alternate Members

REB members, including alternate members, shall work to ensure that all research involving human subjects carried out by, funded by, or otherwise under the auspices of Health Canada or PHAC meets the highest ethical standards and that safeguards are implemented to provide the greatest protection to human subjects, by:

• Undertaking timely ethics reviews of proposed research projects;
• Conducting the continuing ethics review of ongoing research projects, amendments and any adverse events reported by the PIs until the project is completed or terminated;
• Providing their professional recommendations to the Decisional Authority as to whether the research projects should be approved, rejected, modified, or terminated;
• Requesting that additional information be provided by the researchers in order to conclude the ethics review of the research projects;
• Reviewing and monitoring additional information requested by the REB to ensure compliance with the TCPS as well as the REB's Policy and Procedures Manual;
• Assisting in the development of guidelines and procedures for implementing the requirements of the REB's policies consistent with the needs of the relevant research disciplines served by the REB;
• Assisting in the monitoring of the REB's ethics recommendations; and
• Assisting the REB Secretariat in preparing the Annual Report to be submitted to the Decisional Authority.

The members shall be made aware of and are expected to comply with the Treasury Board of Canada's Values and Ethics Code for the Public Service , the TCPS, and the REB's own conflict of interest considerations, as outlined in subsection 5.6 below.

5.4 REB Secretariat

The REB Secretariat shall manage all the administrative affairs of the REB and shall be responsible for:

• Managing all applications received from Health Canada and PHAC;
• Developing the REB's policy framework and administrative procedures for REB and senior management approval;
• Communicating with the PIs on the required revisions to be made to the proposed research project as recommended by the REB;
• Dealing with all communications regarding individual applications submitted to the REB;
• Managing the REB's ongoing administration during and after REB meetings;
• Developing and delivering departmental training programs on the REB; and
• Maintaining the REB website.

5.5 Confidentiality

All REB members are required to protect any confidential or privileged information submitted to the REB for the members' review at monthly REB meetings, or divulged during the day-to-day operations of the REB. Members must not discuss or divulge this information with persons not sitting on the REB until it has been officially released for public distribution.

Documents leaving the REB meetings must be securely stored at all times and any confidential information provided must be returned or securely destroyed. If any such information is knowingly sent to anyone outside of the REB, the REB Secretariat, the offices of the Decisional Authorities, the Office of Public Health Practice, the Office of the DM, or the office of the CPHO, it will be considered a breach of confidentiality and the member's term with the REB will be automatically terminated.

5.6 Conflict of Interest of REB Members

The expression "conflict of interest" refers to situations in which financial, professional, ideological, or other personal considerations may compromise a member's professional judgment in reviewing research projects. Such conflict could affect the member's impartiality or independence.

To help maintain the independence and integrity of the ethics review, it is of the highest importance that members of the REB avoid actual, apparent, perceived or potential conflicts of interest, and comply with the conflict of interest considerations outlined in section 4.1 of the TCPS.

For example, a conflict of interest for REB members may exist under any of the following circumstances:

• When a member's assets, situation or outside activities give rise to the perception that he/she could derive an unfair advantage through working with the REB;
• When a member has a close personal or institutional relationship with the applicant that may create pressure to act against his/her REB-related responsibilities;
• When a member has a personal interest in the research under review or could be exposed to a personal or professional loss or gain as a direct or indirect result of a recommendation made by the REB;
• When a member has a clearly identified position on a specific issue or has had personal or professional differences with the applicant such that their participation in deliberations on the issue could give rise to the perception of bias in the REB recommendations; and
• When a member's own research projects are under review by the REB or when a member has been in direct academic conflict or collaboration with the researcher whose proposal is under review.

A REB member should immediately disclose to the REB Chair and the REB Secretariat any actual, perceived, apparent or potential conflict of interest in regard to a research project. Further, REB members must update their conflict of interest disclosure statements annually, and also as required by a change in circumstances.

5.7 Policy on Indemnification

Pursuant to the Treasury Board's Volunteers Policy , Health Canada/PHAC accept the possibility of the Crown being vicariously liable for the actions of REB members under certain circumstances. However, they also expect members to behave honestly and without malice, exercise due caution, take care of any Crown property entrusted to them, and refrain from any act that could be a cause for disciplinary action if the member were an employee.

Accordingly, it is Health Canada and PHAC policy to:

• Indemnify REB members against personal civil liability incurred by any act or omission within the scope of the member's REB-related activities;
• Make no claim against members based upon such personal liability;
• When they are required to appear before or be interviewed in connection with a judicial, investigative, or other inquest or inquiry;
• When they are sued or charged with an offence; or
• When they are faced with other circumstances that are sufficiently serious to require legal assistance.

6. Meeting Requirements

As stated in Article 1.7 of the TCPS , face-to-face meetings are essential for adequate discussion of research proposals and for the collective education of REB members. The HC-PHAC meetings will be held on a monthly basis except during the summer and the calendar of these meetings shall be posted on the REB website so that researchers can plan their research projects accordingly.

The REB may also hold general meetings, retreats and educational workshops in which members can:

• Participate in educational opportunities that may benefit the overall operation of the REB;
• Discuss any general issues arising out of the REB's activities; and
• Review REB policies and recommend revisions.

Regular attendance by REB members at meetings is important. Members who are frequently absent (i.e. five or more consecutive absences) may be asked to resign by the REB Chair. Special consideration for scheduled absences, i.e. maternal or paternal leave, can be given by the REB.

Researchers may be asked to attend REB meetings to participate in discussions when their research proposals are under review by the REB, but must not be present when the REB makes its final recommendation.

At the REB Chair's discretion, independent consultants with specific expertise in a certain area may be invited to the REB meeting or to provide written comments, subject to the applicable confidentiality agreements.

Recommendations regarding projects requiring full review are made only if a quorum of at least five members exists and if these members possess the range of background and expertise required by the TCPS. Alternate members shall be asked to attend meetings in order to ensure that the required range of expertise and background is available. The Chair, or in his/her absence the Deputy Chair, shall have the final authority to decide whether the quorum has been met.

7. Types of REB Review

7.1 full review, 7.2 expedited review.

Decisions regarding expedited review are at the discretion of the REB Chair or Deputy Chair, for those categories of research that are confidently expected to involve minimal risk to research subjects. Examples of such categories might include:

• Retrospective studies such as chart reviews, reviews of patient records by hospital personnel, etc;
• Studies involving no direct subject contact or reporting only aggregate data;
• Studies dealing only with leftover tissue (however, studies involving fetal waste tissue or genetic material will always require full REB review);
• Studies involving non-invasive product testing or quality assurance activities;
• Annual renewals of approved projects in which there has been little or no change in ongoing research;
• Research protocols that have been previously reviewed and approved by an external REB that is guided by the ethical principles found in the TCPS; or
• Any minor protocol amendment, e.g. administrative changes such as deleting the name of a co-investigator or a change in sponsorship/study budget (however, any amendments likely to affect the rights, safety and/or well-being of the research subjects will always require full REB review).

7.3 Time Sensitive Review

The REB is guided by Article 2.8 of the TCPS when reviewing research in emergency situations. Where REB review is urgently required due to circumstances beyond the researchers' control, the REB Chair or Deputy Chair may also allow an application to be reviewed on a time-sensitive basis via teleconference in one of the following cases:

• Epidemiological studies where incidences of the study target are limited, such as research conducted in the context of an outbreak of a new disease;
• Studies of time limited events; or
• Research whereby a delay caused by waiting for the next REB meeting would place individuals at risk.

8. Elements of the REB Ethics Review

The primary task of the REB lies in the review of research proposals and their supporting documents, with special attention given to the informed consent process, documentation, the suitability and feasibility of the proposed research and protection of privacy and confidentiality. The REB will take into account prior scientific reviews, if any, and the requirements of applicable laws and regulations. The following considerations should be taken into account.

8.1 Scientific Design and Conduct of the Study

• The appropriateness of the study design in relation to the objectives of the study, the statistical methodology (including sample size calculation), and the potential for reaching sound conclusions with the smallest number of research subjects.
• Justification of predictable risks and inconveniences weighed against the anticipated benefits for the research subjects and the concerned communities.
• Criteria for withdrawing research subjects.
• Criteria for suspending or terminating the research.
• Adequacy of provisions made for monitoring the conduct of the research.
• Adequacy of the site, including the support staff, available facilities and emergency procedures.
• The manner in which the results of the research will be reported and published.
• Whether the results of the research can be validated.

8.2 Recruitment of Research Subjects

• The characteristics of the population from which the research subjects will be drawn (including gender, age, literacy, culture, economic status and ethnicity).
• The means by which initial contact and recruitment is to be conducted.
• The means by which full information is to be conveyed to potential research subjects or their representative(s) for the purposes of free and informed consent.
• Inclusion and exclusion criteria for research subjects.
• Whether the requirements for free and informed consent are met, including that it must be voluntarily given, and without a risk of real or perceived manipulation, undue influence or coercion.
• Whether prospective subjects are given assurances that they are free not to participate, and have a right to withdraw at any time without prejudice to pre-existing entitlements.

8.3 Care and Protection of Research Subjects

• Suitability of the qualifications and experience of the investigator(s) for the proposed study.
• Any plans to withdraw or withhold standard therapies for the purpose of the research, and the justification for such action.
• Medical care to be provided to research subjects during and after the course of the research.
• Adequacy of medical supervision and psycho-social support for the research subjects.
• Steps to be taken if research subjects voluntarily withdraw during the course of the research.
• Criteria for extended access to, the emergency use of, or the compassionate use of study products.
• Arrangements, if appropriate, for informing the research subject's general practitioner (family doctor), including procedures for seeking the subject's consent to do so.
• Description of any plan to make the study product available to the research subjects following the research.
• A description of any financial cost to research subjects.
• Remuneration for research subjects (including money, services or gifts) and reimbursement for expenses.
• The provisions for compensation/treatment in the case of the injury/disability/death of a research subject attributable to participation in the research.
• The insurance and indemnity arrangements.

8.4 Protection of Research Subject's Confidentiality

• The persons who will have access to the personal data of the research subjects, including medical records and biological samples.
• Applicable privacy laws (e.g. the Privacy Act ).
• The measures taken to ensure the confidentiality and security of personal information concerning research subjects.

8.5 Informed Consent Process

• The process for obtaining informed consent, including the identification of those responsible for obtaining consent.
• The adequacy, completeness, and clarity of written and oral information to be given to the research subjects and, when appropriate, their legally authorized representative(s).
• Clear justification for the intention to include in the research individuals who cannot consent, and a full account of the arrangements for obtaining substitutive consent for the participation of such individuals from their parents, guardians or other legally authorized representative(s), as appropriate.
• How research subjects will receive information that becomes available during the course of the research relevant to their participation (including their rights, safety and well-being), and be given the opportunity to withdraw at any time without prejudice to pre-existing entitlements.
• Provisions made for receiving and responding to queries and complaints from research subjects or their representative(s) during the course of a research project.

8.6 Community Considerations

• The impact and relevance of the research on the local community and on the concerned communities from which the research subjects are drawn.
• Steps taken to consult with the concerned communities during the course of designing the research.
• Influence of the community on the consent of individuals.
• Proposed community consultation during the course of the research.
• The extent to which the research contributes to capacity building, such as the enhancement of local healthcare, research, and the ability to respond to public health needs.
• The availability and affordability of any successful study product to the concerned communities following the research.
• The manner in which the results of the research will be made available to the research subjects and the concerned communities.

9. REB Ethics Recommendations

The REB operates on the principle of consensus. All REB ethics recommendations require a strong majority and only members who participate in the review shall participate in making the final recommendation. Furthermore, recommendations shall only be made when:

• Sufficient time has been allowed for a review and discussion of an application; and
• The documents required for a review of the application are complete and the relevant elements considered.

All REB ethics recommendations shall be communicated in writing to the PI within 15 days of the meeting at which the recommendation is made. Positive recommendations include a statement of the PI's responsibilities, including:

• Confirming the acceptance of any requirements imposed by the REB;
• Submitting an annual progress report;
• Notifying the REB of protocol amendments (other than amendments involving only logistical or administrative aspects of the study);
• Notifying the REB in the case of amendments to the recruitment material, research subject information, or the informed consent process or form;
• Reporting unforeseen circumstances or the termination of the study; and
• Submitting a final summary report upon completion of the study.

A negative recommendation from the REB shall be supported with reasons.

10. REB Reconsideration and Appeals

10.1 reconsideration of a negative ethics recommendation.

In accordance with Article 1.10 of the TCPS , researchers have the right to request, and the REB has an obligation to provide, a reconsideration of negative recommendations concerning a research project.

Any PI who seeks a reconsideration of a negative recommendation must provide a clear basis for his or her disagreement and a request for reconsideration by the REB. This is to be sent by letter or email to the REB Secretariat within 10 days of receiving notification from the REB of the negative recommendation.

A meeting between the REB and the PI shall be scheduled at the earliest possible REB monthly meeting. At that meeting, the PI shall be invited to further discuss the project with the REB with a view to having the REB reach a decision on the issues that are subject to disagreement, and should bring all relevant documentation that will support the case for reconsideration.

The PI will receive notice from the REB within two weeks of the meeting providing the results of the reconsideration.

10.2 Appeal of a Negative Ethics Recommendation Following Reconsideration

Article 1.11 of the TCPS provides that, in cases when researchers and the REB cannot reach agreement through discussion and reconsideration, an institution should permit review of a REB recommendation by an appeal board, provided that the REB's membership and procedures meet the requirements of the TCPS . No ad hoc appeal boards are permitted.

If an understanding was not reached between the REB and the PI during the reconsideration of the REB's earlier recommendation, the PI can initiate an appeal process within Health Canada/PHAC within 30 days from the date of receiving the notice from the REB providing the results of the reconsideration.

Appeals are not allowed on the grounds that the PI disagrees with the REB on the ethics of the research project. An appeal will only be considered on the grounds of a:

• Perception of bias;
• Lack of due process; or
• Real or apparent conflict of interest.

To initiate an appeal process, the PI must send a letter to the Decisional Authority and the REB Secretariat setting out the basis for the appeal and supporting evidence. Upon receipt of the appeal letter, the Decisional Authority will call upon the Appeal Board to meet within two months. The Appeal Board composition shall reflect the expertise profile of the REB, but REB members shall not sit on the Appeal Board.

The Appeal Board can seek assistance from other experts in fields relevant to the appeal. The PI and the REB Chair will be invited to present their evidence to the Appeal Board. The Appeal Board will consider all relevant evidence before advising the Decisional Authority as to whether there was a failure in the REB's ethics review process for the project under appeal. The Decisional Authority will, in turn, advise the Deputy Minister/CPHO.

If the Deputy Minister/CPHO finds that a failure in the ethics review process has occurred, the project will be referred back to the REB for a further ethics review. If he/she does not find a failure in the REB ethics review process, the recommendation made by the REB will stand. The Deputy Minister/CPHO's decision is final and binding on the PI who requested the appeal.

11. Continuing Ethics Review

The REB will review each study that has been the subject of a positive ethics recommendation and received subsequent approval until termination of the research. Approved studies will be reviewed at least annually, though the REB may require more frequent reviews based on the nature, potential risks and planned milestones of a research project. The following shall require follow-up review:

• Protocol amendments likely to affect the rights, safety or well-being of the research subjects or the conduct of the study;
• Serious and unexpected adverse events related to the study; and
• Any event or new information that may affect the benefit/risk ratio of the study.

Any decision arising from a follow-up review must be issued and communicated by the Decisional Authority to the PI, indicating a modification, suspension, or termination of the REB's original recommendation, or confirming that the original recommendation is still valid.

12. Annual Report

The REB Chair shall report on an annual basis to the Decisional Authority. This Annual Report shall be made publicly available on the REB website.

13. Documentation and Archiving

All documentation and communication of the REB shall be dated, filed and archived for a minimum period of 15 years following the completion of a study. These include:

• Written standard operating procedures of the REB and annual reports;
• Curriculum vitae of all REB members;
• A record of all income and expenses of the REB;
• Published guidelines for submission established by the REB;
• Agenda of the REB meetings;
• Minutes of the REB meetings;
• One copy of all materials submitted by an applicant;
• The correspondence by REB members with applicants or concerned parties regarding an application, decision and follow-up;
• A copy of the recommendation and any advice requirements sent to an applicant;
• All written documentation received during a follow-up;
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Canada’s new ethical guidelines for research with humans: a critique and comparison with the United States

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Canada’s Tri-Council Policy Statement: Ethical conduct for research involving humans, first published in 1998, has recently been updated. 1 The US Department of Health and Human Services has just issued an Advance Notice of Proposed Rulemaking that would substantially change the 20-year-old Common Rule governing most federally funded research involving human participants. 2 A comparison of the two countries’ systems for protecting human research participants is therefore timely. This analysis situates the Canadian system in an international context, with particular attention to its similarities and differences to the US system and their shared challenges going forward with their changes.

• Systems of oversight for research with humans

Prior review of research proposals by a research ethics committee according to legally binding standards is the primary means used around the world to protect research participants. In Canada and the United States, the institutions that conduct research are responsible for its review. As a result, most academic centres have their own research ethics committee — a research ethics board in Canada or an institutional review board in the US. Similar institutional models are followed by other developed countries, such as Australia and Japan. By contrast, regional models — in which a research ethics committee reviews all the research conducted in a particular geographic area — are common in Europe.

In Canada, any institution that receives funding from one of the three federal granting agencies — the Canadian Institutes of Health Research, the Social Sciences and Humanities Research Council, and the Natural Sciences and Engineering Research Council of Canada —must ensure that all research involving humans conducted at that institution complies with the Tri-Council Policy Statement. Health Canada also requires that sponsors of clinical trials of drugs and devices obtain approval from a research ethics board, and two provinces (Quebec, and Newfoundland and Labrador) require ethics review for some or all of the research that takes place within them. 3 , 4 However, the Tri-Council Policy Statement is the primary source of concrete guidance regarding the ethical oversight of research with humans in Canada. From its inception, the statement has been intended to be a “living, evolving document that reflects developments in research and research ethics.” 5 Hence the current revisions.

In the US, most research involving human participants funded by federal government agencies is subject to the Common Rule — a set of regulations delineating the requirements for review by an institutional review board. 6 Similar rules apply to research regulated by the Food and Drug Administration (FDA). 7 Although US institutions could decline to apply the Common Rule to research that does not receive federal funding, relatively few do so. 8 The reforms proposed in the recent Advance Notice of Proposed Rule-making have two goals. First, to improve the effectiveness of the system of federal oversight, for example, by reducing the amount of time spent reviewing low-risk research and by allowing only one institutional review board of record for multisite studies. 9 Second, to enhance protections for research participants, for example, by imposing uniform standards of security of data and requiring all research at institutions receiving funding from Common Rule agencies to follow the Common Rule (just as the Tri-Council Policy Statement does for Canada).

In both systems, then, ethics review of research is necessary if funding is received from the federal government or regulatory approval of new drugs and devices is sought. Again, this differs from many other countries, where all research with human participants within their borders may be required to undergo review. For example, the European Clinical Trials Directive applies to all clinical trials, irrespective of source of funding or other contact with government bodies. 10

The institutional model of review has the advantages that members of the research ethics committee are more likely to be familiar with the research they review, monitoring of ongoing research is easier and it is possible to impose institutional sanctions for violations by investigators. However, this model has several drawbacks. First, conflicts of interest are more likely because the institution hosting the research ethics committee has an interest in the research proceeding, and members of the research ethics committee may be colleagues of the researchers. 11 Second, an increasing amount of research now takes place at multiple sites. 12 In Canada and the US, because institutions are held liable for regulatory breaches, this usually entails a research ethics committee at each site reviewing the research proposal. Multiple reviews take up time and resources, and researchers complain of inconsistent judgments from research ethics committees that mandate minor changes without improving protections for research participants. 13 , 14

Use of government funding or contact with regulatory agencies as the way to ensure ethics review carries the risk of ethically problematic research falling through the cracks. For example, pharmaceutical companies may conduct research that is not part of marketing applications, and experimentation with surgical techniques may not use novel drugs or devices. Stories of people being enrolled in risky research without protections has led to calls in the US for a nationwide law requiring ethics review. 15 , 16

This method of ensuring ethics review can also lead to research falling under multiple sets of regulations. For example, the US federal government funds a substantial amount of research involving human participants abroad, including in Canada (e.g., in 2010 the National Institutes of Health gave nearly US$64 million in direct grants to Canadian institutions). 17 Because of the funding source, the researchers must follow the Common Rule; but at Canadian institutions they must simultaneously follow the Tri-Council Policy Statement. The same concern arises when researchers from Canadian institutions conduct research abroad.

Where possible, the Tri-Council Policy Statement and the Common Rule do attempt to address these problems. The Tri-Council Policy Statement has considered conflicts of interest, including conflicts of interest for members of research ethics boards, since 1998. 18 The updated statement extends its analysis of conflicts of interest and the measures that should be taken to address them, for instance, by addressing conflicts of interest for institutions and institutional officials. With regard to multiple reviews, both Canadian and US rules permit institutions to rely on outside research ethics committees, although relatively few institutions currently use this option. 19 However, experiments with centralizing review — such as the US National Cancer Institute’s Central Institutional Review Board and the Ontario Cancer Research Ethics Board — have had broadly positive results. 20 , 21 An analysis of centralized and noncentralized review in five English-speaking countries suggested that centralizing at least the administrative aspects of ethics review is helpful in reducing delays and excessive work from multisite trials. 22 Moreover, one key change in the US Advance Notice of Proposed Rulemaking would require there to be just one institutional review board of record for all domestic sites involved in a multisite study. Multijurisdictional research has its own chapter in the updated Tri-Council Policy Statement, which includes extensive discussion of a range of different models for review by research ethics boards of multisite research.

The problem of having both sets of regulations apply to research in Canada funded by the US government could also be solved under the current regulations. For research at institutions in foreign countries that follow different procedures for protecting human participants, the Common Rule states the following:

if a department or agency head determines that the procedures prescribed by the institution afford protections that are at least equivalent to those provided in this policy [the Common Rule], the department or agency head may approve the substitution of the foreign procedures in lieu of the procedural requirements provided in this policy. 23

However, despite the development of a method for determining whether a set of procedures offers “equivalent protections,” this option has never been taken. 24

The problems just noted stem from structural features of the systems of review. In some instances, documents like the Tri-Council Policy Statement can be helpful. For example, a future revision could follow the Advance Notice of Proposed Rulemaking and require that only one research ethics board conduct most of the review for multisite studies. In other instances, however, legislative action would be needed to change the systems in ways that would address the problems. For example, as it stands, the Tri-Council Policy Statement does all that it can to ensure that potentially risky research undergoes review — the Tri-Council agencies do not have the power to require review at institutions where they do not fund research. That would require provincial or national legislation.

• The process of ethical review

Like the ethics review systems in other countries, the Canadian and US systems have provoked criticism from researchers for inappropriately applying biomedical models to research from other disciplines and for requiring low-risk research to undergo excessive scrutiny.

The Common Rule was written in response to abuses by biomedical researchers and designed to regulate biomedical research. Nonetheless, it applies to any research that involves obtaining data through “intervention or interaction” with living persons, and review by institutional review boards of humanities and social science research is now common. The Tri-Council Policy Statement was explicitly intended to cover nonbiomedical research. However, in both countries, some social science researchers complain that a biomedical model is inappropriately imposed on their discipline with a potentially chilling effect on important research. 25 , 26 The updated Tri-Council Policy Statement places greater emphasis than its predecessor on distinguishing the standards that should apply to different types of research; for example, it now has separate chapters discussing qualitative research and clinical trials. It is also the result of an extensive process of consultation, including with academics in the social and behavioural sciences, and, as a Tri-Council statement, has been endorsed by the Social Sciences and Humanities Research Council.

Both jurisdictions exempt some research with humans from review, and countenance an expedited or delegated form of review for some research involving “minimal risk” whereby the review is conducted by just one or two members of a research ethics committee. Nevertheless, full review by a research ethics committee is common even for research that falls into one of these categories. 27 , 28 One of the changes proposed by the US Advance Notice of Proposed Rulemaking would attempt to address this problem by excusing a wider category of studies from review, including all studies whose risks are mostly informational, provided that they adhere to strict standards for data security and confidentiality. Crucially, researchers engaged in excused research would be permitted to begin research immediately after registering their study with the institutional review board, so as to avoid the current situation where many institutions require some prior review of purportedly exempt studies to ensure that they are exempt.

The updated Tri-Council Policy Statement continues to place more emphasis on flexibility than the Common Rule (although the Advance Notice of Proposed Rulemaking offers some ways to make the scrutiny of research proposals more proportionate to levels of risk than at present). The updated statement consistently emphasizes the importance of a “proportionate approach to research ethics review” 29 according to which the most risky research receives the “most intensive scrutiny, time and resources.” 30 Moreover, individual institutions are granted considerable leeway in deciding how to institute this proportionate approach, who may carry out delegated reviews and so forth. This flexibility is a model for others to follow, and Canadian institutions should make the most of it — the resources for ethics review are always limited, so they should be used to focus on the research most likely to raise ethical concerns. 31

• The Tri-Council Policy Statement

Its significantly greater length allows the Tri-Council Policy Statement to address many more ethical issues than the Common Rule. Although guidance on specific questions is periodically issued by the FDA or the Office for Human Research Protections, the US does not have regulatory requirements covering so many key issues. 32 The updated Tri-Council Policy Statement mostly consists of changes or additions, which have nearly doubled its size. 33 These include further guidance on research involving Aboriginal people, incidental findings relevant to participants’ health, conflicts of interest and research during emergencies. The additions reflect ethical issues that have become much more prominent over the last decade. The updated statement also casts its net more widely to cover more than just the protection of research participants. For instance, like the 2008 Declaration of Helsinki, it now requires the registration of clinical trials before recruitment begins. 34

The core principles of the Tri-Council Policy Statement have been radically revised. According to the first version of the statement, respect for human dignity was the foundational principle of research ethics. Somewhat confusingly, it was also one of eight guiding ethical principles. The updated version consolidates these principles to three — respect for persons, concern for welfare, and justice. These correspond to the principles underlying the US regulations as stated in the Belmont Report. 35 The updated Tri-Council Policy Statement purports to retain “respect for human dignity” as its “underlying value.” However, the concept does not do any real work independent of the core principles.

The new approach is an improvement: the three principles better reflect the content of ordinary moral thought. Ethical dilemmas that people face in all areas of life — not just in research — involve the consideration of how to respect people’s rights, balance benefits and harms, and treat people fairly. Moreover, none of these three principles can be assimilated to any of the others; for example, it is important to respect someone’s autonomous decisions, even if they are likely to negatively affect his or her welfare. Hence, these three principles are both central and basic to moral thought.

• Substantive disagreements

The original Tri-Council Policy Statement and the US regulations differed on several issues, most notably on the use of placebo controls and research with children. These disagreements remain. The US FDA permits placebo controls even when there exists an effective treatment for the condition being studied in a wide range of cases in which use of placebo is deemed scientifically necessary. 36 The updated Tri-Council Policy Statement is much more restrictive. The only instance it suggests in which it would be permissible to randomly assign participants to placebo when a proven treatment for those participants exists is when “patients have provided an informed refusal of established effective therapy” before recruitment. 37 This is strict in comparison to even the Declaration of Helsinki, which now allows the use of placebos when an effective treatment exists if there are “compelling and scientifically sound methodological reasons” for using placebo, and participants will not be at risk of serious harm. 38

The updated Tri-Council Policy Statement permits research with children only when it poses minimal net risk to participants. This is consistent with international guidelines such as the Declaration of Helsinki. 39 In the US, children may be enrolled in research that involves a “minor increase over minimal risk” with no prospect of direct benefit if the research is expected to produce important knowledge about the participants’ disorder or condition. 40 There is even provision for the approval of riskier research in exceptional circumstances. 41

With these rules strictly applied, one would expect these differences to lead to different research being conducted in the two countries and to impede some collaborative research. If they have not, it might illuminate the practice of review by research ethics committees to investigate why.

• Looking forward

The updated Tri-Council Policy Statement improves on the guidance of its predecessor and expands on ethical issues that were less prominent in 1998. It should also prove a useful resource in the US, where institutional review boards sometimes lack clear guidance on the novel ethical issues they face. However, the biggest problems for both systems concern the implementation of the rules, not their content. Many of these problems — such as conflicts of interest in research ethics committees, underreview and overreview — are related to the institution-based model of ethical review in both countries. For the most part, guidance and regulatory resources, like the Tri-Council Policy Statement, address these problems, but their suggested solutions require work by institutions and government agencies to implement them effectively. Either greater efforts to implement them are needed, or stricter rules — like those now proposed for multisite review in the US —must be imposed.

The updated Tri-Council Policy Statement has nearly doubled in length and improves on its 1998 predecessor.

The recent US Advance Notice of Proposed Rulemaking suggests substantial changes to the Common Rule.

Canada and the United States have similar systems of ethical review with similar problems.

The problems that have not been addressed thus far mostly concern the application and scope of rules, not their content.

• Acknowledgements

The author thanks Kirstin Borgerson and Jim Lavery for helpful comments on an earlier draft of this manuscript.

Competing interests: None declared.

This article has been peer reviewed.

Disclaimer: The opinions expressed are those of the author and do not reflect the position or policy of the National Institutes of Health, the Public Health Service or the Department of Health and Human Services.

• ↵ Tri-council policy statement: ethical conduct for research involving humans . Ottawa (ON) : Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada ; 2010 .
• ↵ Food and Drug Administration and the Office of the Secretary . Human subjects research protections: enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators . Washington (DC) : US Department of Health and Human Services ; 2011 .
• ↵ Arts 20 and 21 CCQ.
• ↵ Health Research Ethics Authority Regulations under the Health Research Ethics Authority Act, NL R 57/11.
• ↵ Government of Canada . About the TCPS . Panel on Research Ethics . Available: www.pre.ethics.gc.ca/eng/panel-group/faq/tcps-eptc/ ( accessed 2011 Oct. 3 ).
• ↵ Protections of human subjects, 45 CFR part 46, subpart A (1991). Revised Jan. 15, 2009; effective July 14, 2009.
• ↵ Food and Drugs, 21 CFR parts 50 and 56 (2010). Chapter I: Food and Drug Administration, Department of Health and Human Services. Subchapter A: General. Revised as of Apr. 1, 2011.
• Thomson J ,
• Emanuel EJ ,
• ↵ EC, Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, [2001] OJ, L 121/34.
• McWilliams R ,
• Hoover-Fong J ,
• Gunsalus CK
• ↵ Ethical and policy issues in research involving human participants . Volume I: report and recommendations of the National Bioethics Advisory Commission . Washington (DC) : National Bioethics Advisory Commission ; 2001 .
• ↵ National Institutes of Health . Research Portfolio Online Reporting Tools (RePORT) . Washington (DC) : US Department of Health and Human Services ; 2011 . Available: http://projectreporter.nih.gov/reporter.cfm ( accessed 2011 Oct. 3 ).
• ↵ Tri-Council policy statement: ethical conduct for research involving humans . Ottawa (ON) : Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada ; 1998 (with 2000, 2002 and 2005 amendments).
• Sobolski GK ,
• Wagner TH ,
• Goldberg J ,
• Fitzgerald MH ,
• Phillips PA
• ↵ Protections of human subjects, 45 CFR §46.101(h). Revised Jan. 15, 2009; effective July 14, 2009.
• Lavery JV ,
• McDonald M ,
• ↵ Social Sciences and Humanities Research Ethics Special Working Committee . Giving voice to the spectrum . Interagency Advisory Panel and Secretariat on Research Ethics ; 2004 . Available: www.sfu.ca/~palys/SSHWC-GivingVoice-2004.pdf ( accessed 2011 Dec. 6 ).
• Bledsoe CH ,
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• ↵ Tri-Council policy statement: ethical conduct for research involving humans [article 6.12] . Ottawa (ON) : Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada ; 2010 .
• ↵ Tri-Council policy statement: ethical conduct for research involving humans [article 2.9] . Ottawa (ON) : Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada ; 2010 .
• ↵ Office for Human Research Protections . Policy and guidance . Washington (DC) : US Department of Health and Human Services . Available: www.hhs.gov/ohrp/policy/index.html ( accessed 2011 Dec. 6 ).
• ↵ Tri-Council policy statement: ethical conduct for research involving humans. [table of concordance] . Ottawa (ON) : Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada ; 2010 .
• ↵ World Medical Association . Declaration of Helsinki . Ferney-Voltaire (France) : The Association ; 2008 .
• ↵ The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research . The Belmont report: ethical principles and guidelines for the protection of human subjects of research . Washington (DC) : The Commission ; 1979 .
• Ellenberg SS
• ↵ Tri-Council policy statement: ethical conduct for research involving humans [article 11.2] . Ottawa (ON) : Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada ; 2010 .
• ↵ World Medical Association . Declaration of Helsinki [principle 32] . Ferney-Voltaire (France) : The Association ; 2008 .
• ↵ World Medical Association . Declaration of Helsinki [principle 27] . Ferney-Voltaire (France) : The Association ; 2008 .
• ↵ Protections of human subjects, 45 CFR §46.406. Revised Jan. 15, 2009; effective July 14, 2009.
• ↵ Protections of human subjects, 45 CFR §46.407. Revised Jan. 15, 2009; effective July 14, 2009.

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Ethics protocols are reviewed by one of the following University of Toronto (U of T) Research Ethics Boards REBs, depending on the departmental or faculty affiliation of the Principal Investigator (PI).

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The Secretariat on Responsible Conduct of Research (SRCR)

The Secretariat on Responsible Conduct of Research is mandated to, among other things, provide substantive and administrative support to the Panel on Research Ethics and the Panel on Responsible Conduct of Research.

Secretariat on Responsible Conduct of Research Telephone: 343-803-4358 Toll Free: 1-888-366-3851 [email protected]

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The Secretariat on Responsible Conduct of Research (SRCR or Secretariat) (formerly, Secretariat on Research Ethics) provides substantive and administrative support for the Panel on Research Ethics (PRE), the Panel on Responsible Conduct of Research (PRCR), and for the three federal research granting Agencies (CIHR, NSERC and SSHRC) with respect to the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans , 2nd edition (TCPS 2), and the Tri-Agency Framework: Responsible Conduct of Research (the Framework).

The mandate of the Secretariat with respect to PRE, PRCR and the Agencies is to:

• promote high ethical standards in the responsible conduct of research;
• learn from and respond to emerging issues in research ethics and responsible conduct of research, in a national and international context;
• provide interpretations, as requested, of the TCPS 2 and the Framework for their implementation and use;
• recognize the diversity of approaches used in research involving humans;
• foster awareness and understanding of research ethics issues among researchers, research institutions, members of REBs, and the public;
• participate in the ongoing national discussion regarding the development of an oversight system for research ethics review practices;
• implement and promote educational activities related to the implementation of the TCPS 2 and the Framework; identify concerns or issues that may arise as part of these activities and inform PRE or PRCR should these issues warrant any modification or clarification of the TCPS 2 or the Framework;
• participate in the ongoing national dialogue regarding the responsible conduct of research;
• foster awareness and understanding of responsible conduct of research among researchers and research institutions through education and training; and
• establish and sustain collaborative relationships with other organizations.

For PRE, the Secretariat provides administrative, substantive and communication support by:

• managing incoming requests for interpretation of the TCPS 2;
• arranging for expert advice on substantive questions of interpretation, as needed, for PRE;
• issuing and disseminating official interpretations of the TCPS 2 to develop a publicly accessible bank of precedents;
• monitoring requests for interpretation over time to identify trends, gaps or difficulties in the TCPS 2 and communicating these to PRE for action;
• coordinating and supporting PRE's meetings;
• communicating PRE's decisions and highlights of their meetings, to the broader community in an open and transparent manner; and
• implementing and promoting educational outreach with respect to the ethical conduct of research involving humans to the research community.

For PRCR, the Secretariat provides administrative, substantive and communication support by:

• managing allegations of breaches of Agency policies;
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• reviewing institutional investigation reports to ensure the process followed by the institution is in accordance with its own responsible conduct of research policy and is consistent with the Framework;
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• implementing and promoting educational outreach with respect to the responsible conduct research to the research community.

The Secretariat supports the Agencies by:

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• coordinating and supporting the meetings of the Interagency Management Committee and the Steering Committee; and
• Maintaining web sites for PRE and PRCR.

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The Secretariat collaborates with other national organizations, such as the Canadian Association of Research Ethics Boards, the Canadian Association of University Research Administrators, the Canadian Federation for the Humanities and Social Sciences, and the Canadian Research Integrity Forum, among others.

The Secretariat also has the option to engage in activities through outsourcing, which benefits the process by involving a larger expert constituency in the evolution, interpretation, education and implementation of the TCPS 2 and the Framework.

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The Executive Director of the Secretariat reports to the Advisory Panel on Research Ethics and the Advisory Panel on Responsible Conduct of Research through their respective Chairs primarily on policy matters, and to the Interagency Management Committee (IMC) primarily on interagency administrative and operational matters.

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Research ethics board, introduction.

In 2001, three federal research agencies, the Natural Sciences and Engineering Research Council (NSERC), the Social Sciences and Humanities Research Council (SSHRC) and the Canadian Institutes of Health Research (CIHR), jointly created the Interagency Advisory Panel on Research Ethics (PRE) as part of a collaborative effort to promote the ethical conduct of research involving human participants.

The PRE examines when the  Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans , or " TCPS 2 ," should be applied, and reviews the goals and rationale of the policy. It defines the guiding ethical principles of the TCPS. It discusses the way these principles are applied in practice and introduces the relationship between the TCPS and the law. All protocols submitted to the Board must be consistent with these guidelines.

As a consequence, all research involving human subjects at the Royal Military College (RMC) of Canada or elsewhere conducted by or administered to RMC students, post-doctorate fellows, staff and faculty must be reviewed to assess its compliance with the TCPS. The Research Ethics Board (REB) of RMC has been established to review all research conducted at or for the College that involves humans.

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

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

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

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

Contact Information

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

Office of Clinical Trials Pharmaceutical Drugs Directorate Health Products and Food Branch Address Locator: 3105A Health Canada Ottawa, Ontario, Canada K1A 0K9

Phone (General Enquiries): 613-957-0368 Fax (General Enquiries): 613-952-7756 Office of Clinical Trials Inquiries: [email protected]

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

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

Phone: 613-863-8405 General Enquiries E-mail: [email protected]

This profile covers the role of the Department of Health & Human Services (HHS) ’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct , 21CFR50 , and 21CFR312 . Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule ( Pre2018-ComRule and RevComRule ), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E . (Please note: ClinRegs does not provide information on state level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct , 21CFR50 , and 21CFR312 , the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92 , the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33 . Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) . Additionally, per USA-88 , the Office of Clinical Policy (OCLiP) develops good clinical practice and human subject protection policies, regulation, and guidance.

See USA-47 for a list of FDA clinical trials related guidance documents.

Office for Human Research Protections and Common Rule Agencies

Per USA-93 , the OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule ( Pre2018-ComRule and RevComRule ) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-65 for a list of US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65 ), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-55 and USA-74 , the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements decision charts consistent with the RevComRule , including how to determine if research is exempt, see USA-74 . For more information about the RevComRule , see USA-66 .

Per the RevComRule , the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65 ) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule . Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements decision charts consistent with the Pre2018-ComRule , including how to determine if research is exempt, see USA-74 .

See USA-54 for additional information regarding compliance with the Pre2018-ComRule and the RevComRule .

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50 . However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

Other Considerations

Per USA-16 , the US is a founding regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The US has adopted several ICH guidance documents, including the E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population ( US-ICH-E11 ), E17 General Principles for Planning and Design of Multiregional Clinical Trials ( US-ICH-E17 ), and E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) ( US-ICH-GCPs ), which are cited throughout this profile.

As per USA-81 , USA-91 , and USA-90 , the contact information for the FDA is as follows:

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Telephone (general inquiries): (888) 463-6332

CDER Telephone (drug information): (301) 796-3400 CDER Email: [email protected]

CBER Telephone: (800) 835-4709 or (240) 402-8010 CBER Email (manufacturers assistance): [email protected] CBER Email (imports): [email protected] CBER Email (exports): [email protected]

Office for Human Research Protections

Per USA-82 , the contact information for the OHRP is as follows:

Office for Human Research Protections 1101 Wootton Parkway, Suite 200 Rockville, MD 20852 Telephone: (866) 447-4777 or (240) 453-6900 Email (general inquiries): [email protected]

Department of Health & Human Services

According to USA-83 , the contact information for the HHS is as follows:

US Department of Health & Human Services Hubert H. Humphrey Building 200 Independence Avenue, S.W. Washington, D.C. 20201 Call Center: (877) 696-6775

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
• 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.

In accordance with the FDCAct , 21CFR50 , and 21CFR312 , the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312 , institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42 , sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42 , the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.
• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD , non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination , in general, human research studies must be conducted under an IND if all of the following research conditions apply:

• A drug is involved as defined in the FDCAct
• A clinical investigation is being conducted as defined in 21CFR312
• The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct .

Further, per 21CFR312 and the G-IND-Determination , whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

As delineated in 21CFR312 , the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94 , the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312 , an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312 for more information on clinical holds.

According to USA-41 , with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312 , the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, on the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312 , if no subjects are entered into a clinical study two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95 , respectively.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

• Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
• Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
• Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
• Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct , as amended by the FDORA , for changes to the accelerated approval process.

The G-RWDRWE-Reg , issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17 ), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials .

For research involving cellular and gene therapy, see the guidance documents at USA-80 .

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

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct , FDARA , and USA-45 , the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). Per USA-43 , the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA.

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.

As indicated in 21CFR50 , 21CFR56 , and 21CFR312 , the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50 , 21CFR56 , and 21CFR312 , all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule , for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule . Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

As stated in 21CFR56 , the Pre2018-ComRule , and the RevComRule , an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

• One (1) primarily focused on scientific issues
• One (1) focused on nonscientific issues
• One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.

As delineated in 21CFR56 , ECs must follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , ECs must establish and follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
• Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, the institution, the FDA, and the Department of Health & Human Services (HHS) ’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination.

21CFR56 , the Pre2018-ComRule , and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule , the RevComRule , and 21CFR56 .

See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56 , the Pre2018-ComRule , and the RevComRule , proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule , the RevComRule , 21CFR56 , the G-IRBProcs , and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule , the RevComRule , and the G-HHS-Inst-Engagemt , any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65 ) must also submit a written assurance of compliance to OHRP. According to USA-59 , the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-funded research. See USA-57 for more information on FWAs.

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.

21CFR56 , 21CFR312 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56 , the Pre2018-ComRule , and the RevComRule , the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

In accordance with 21CFR56 and 21CFR312 , the Food & Drug Administration (FDA) must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56 , the Pre2018-ComRule , and the RevComRule , the EC may approve, require modifications in (to secure approval), or disapprove the research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the Department of Health & Human Services (HHS) that must also comply with FDA regulations.

Per 21CFR56 , the Pre2018-ComRule , the RevComRule , and the G-IRBContRev , an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

Expedited Review

21CFR56 , the Pre2018-ComRule , and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

• Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
• Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
• Under the RevComRule , research for which limited EC review is a condition of exemption

21CFR56 , the Pre2018-ComRule , and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev , research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev .

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

• Research eligible for expedited review
• Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
• Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule , certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Per USA-54 , for secondary research that does not qualify for an exemption under the RevComRule , the applicant must either apply for a waiver of the informed consent requirement from the EC, obtain study-specific informed consent, or obtain broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

• Scholarly and journalistic activities
• Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
• Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

See the G-IRBFAQs , the G-OHRP-IRBApprvl , and USA-54 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.

Per the FDA’s G-IRBReview , an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview .

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule , the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-65 ) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule , per the NIHNotice16-094 and the NIHNotice17-076 , the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see the FDA’s G-CoopRes . For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS Office for Human Research Protections (OHRP) ’s G-ComRuleCnsstncy .

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 .

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

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

As delineated in 21CFR56 and 45CFR46-B-E , the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system ( USA-28 ) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP) .

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61 , EC registration with the HHS OHRP system ( USA-28 ) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56 , or by the HHS that the EC is in full compliance with 45CFR46-B-E . Neither EC competence nor expertise is assessed during the registration review process by either agency.

According to 21CFR56 and the G-IRBReg-FAQs , the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system ( USA-28 ). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs , any EC not already registered in the HHS OHRP system ( USA-28 ) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system ( USA-28 ) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements. See the G-IRBInspect for FDA inspection procedures of ECs.

Per the Pre2018-ComRule and RevComRule , institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-65 ) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59 , a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects ( Pre2018-ComRule or RevComRule ) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

Per USA-54 , institutions do not need to change an existing FWA because of the RevComRule . See USA-57 for more information on FWAs.

Per 45CFR46-B-E and USA-61 , all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system ( USA-28 ). An individual authorized to act on behalf of the institution operating the EC must submit the registration information. EC registration becomes effective for three (3) years when reviewed and approved by OHRP.

Per USA-59 , an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E , USA-58 , and USA-61 for detailed registration requirements and instructions.

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 [email protected] ; 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 [email protected] ; 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
• 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: [email protected]

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: [email protected]

Per the HCNotice-CTSIForm , questions related to pharmaceutical CTSI forms should be sent to: [email protected] and questions related to biologic CTSI forms should be sent to [email protected] .

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.

As delineated in 21CFR312 , USA-42 , and USA-52 , the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA) 's review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination , whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct ) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312 , institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

According to 21CFR312 , meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA .

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to the G-PharmeCTD , which implements FDCAct requirements, and as described in USA-34 and USA-53 , commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) . See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD , the G-eCTDTech , USA-35 , and USA-36 . Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs and USA-7 , eCTD submissions sized 10 GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (ESG) ( USA-44 ). However, the G-eCTDspecs adds that the FDA also recommends the use of USA-44 for submissions greater than 10 GB when possible. See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs , physical media greater than 10 GB should be submitted using a USB drive. For specific instructions on how to submit physical media, email CDER at [email protected] or CBER at [email protected] . See the G-eCTDspecs for additional physical media information.

The IND must be submitted in English. As indicated in 21CFR312 , the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

According to USA-41 and USA-94 , paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration Center for Drug Evaluation and Research (CDER) Central Document Room 5901-B Ammendale Rd. Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators) :

Food and Drug Administration Center for Drug Evaluation and Research (CDER) Therapeutic Biological Products Document Room 5901-B Ammendale Rd. Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration Center for Biologics Evaluation and Research (CBER) Document Control Center 10903 New Hampshire Avenue WO71, G112 Silver Spring, MD 20993-0002

(Note: Per USA-94 , CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

Based on information provided in 21CFR312 , for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports.

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

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:

• 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
• 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
• 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 .

As specified in 21CFR312 , an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

• Cover sheet (Form FDA 1571 ( USA-76 )) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
• Table of contents
• Introductory statement and general investigational plan
• Investigator’s brochure (IB)
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the IP
• Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
• Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312 . In addition, see USA-40 for other IND forms and instructions.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials .

The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc .

The FDCAct , as amended by the FDORA , requires sponsors to submit diversity action plans for certain clinical trials, such as a clinical investigation of a new drug that is a phase 3 study. See the FDORA for more details. (Note: The FDA’s guidance on diversity action plans is currently in draft. The ClinRegs team will continue to monitor this requirement and incorporate any updates as appropriate).

According to the G-PedStudyPlans , a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA) . An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans .

Each EC has its own application form and clearance requirements, which can differ significantly regarding application content requirements. However, the requirements listed below comply with 21CFR56 as well as the US-ICH-GCPs and are basically consistent across all US ECs.

As per 21CFR56 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• Informed consent forms (ICFs) and participant information (the RevComRule also requires information regarding whether informed consent was appropriately sought and documented, or waived)
• Investigator(s) current Curriculum Vitaes (CVs)
• Additional required EC documentation
• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate; the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data

Per the RevComRule , where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56 , the Pre2018-ComRule , the RevComRule , and section 3 of the US-ICH-GCPs for additional EC submission requirements.

According to the US-ICH-GCPs , the clinical protocol should contain the following elements:

• Participant selection/withdrawal
• Quality control/quality assurance
• Data handling/recordkeeping
• Financing/insurance
• Publication policy
• For complete protocol requirements, see section 6 of the US-ICH-GCPs .

Per the NIHNotice17-064 , and provided in USA-29 and USA-27 , the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

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.

As delineated in 21CFR56 and 21CFR312 , institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA) 's review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Per the FDCAct and 21CFR312 , initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312 , the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95 , respectively.

According to USA-41 and USA-42 , clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial. However, according to the US-ICH-GCPs , the institutional EC should review a proposed clinical trial within a reasonable time.

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.

In accordance with 21CFR312 , USA-41 , and USA-42 , a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA) , which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56 , ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312 , once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTDiversity for FDA recommendations to sponsors on increasing enrollment of underrepresented populations in their clinical trials.

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs , the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 ( USA-77 ). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312 , the G-1572FAQs , and USA-40 for further information.

The US-ICH-GCPs indicates that the sponsor must obtain the investigator’s/institution’s agreement:

• To conduct the trial in compliance with good clinical practice (GCP), 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/reporting;
• To permit monitoring, auditing, and inspection; and
• 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 must sign the protocol, or an alternative document, to confirm this agreement.

The FDAMA , the FDAAA , and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank ( USA-78 ). Per the FDAAA and 42CFR11 , the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov ( USA-78 ).

See 42CFR11 , the NIHTrialInfo , and USA-49 for detailed information on ClinicalTrials.gov ( USA-78 ). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

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 t he ElecSubms . For technical questions on eCTD filings, contact [email protected] as instructed in t he G-DSUR . Per the Non-eCTDformat , DSURs in "non-eCTD electronic-only" format should be sent via email to [email protected] for biologic and radiopharmaceutical drugs and [email protected] 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".

In accordance with 21CFR312 , the G-IND-Safety , 42CFR11 , and USA-38 , the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US):

• Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
• Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
• Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
• Serious Adverse Event/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
• Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
• Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs , the Department of Health & Human Services (HHS) ’s 45CFR46 regulations (the Pre2018-ComRule , the RevComRule , and 45CFR46-B-E ) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs , the G-IRBRpting , the Pre2018-ComRule , and the RevComRule for further information.

As delineated in 21CFR312 and the G-IND-Safety , the investigator must comply with the following reporting requirements:

• Serious adverse events, whether or not considered drug related, must be reported immediately to the sponsor
• Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
• Non-serious adverse events must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others where adverse events should be considered unanticipated problems

As delineated in 21CFR312 , the G-IND-Safety , and USA-38 , the sponsor must report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event .

The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312 and the G-IND-Safety , the sponsor must also report the following:

• Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report), whether or not conducted under an investigational new drug application (IND), and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312 and the G-IND-Safety for more details on these safety reporting requirements.

As part of the clinical trial results information submitted to ClinicalTrials.gov ( USA-78 ), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:

• All serious adverse events
• All adverse events, other than serious adverse events, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11 and USA-70 , this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov ( USA-78 ) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

See 42CFR11 for detailed adverse event reporting requirements.

As per 21CFR312 , the G-IND-Safety , and USA-38 , the sponsor must submit each safety report in a narrative format on Form FDA 3500A ( USA-75 ), or in an electronic format that the FDA can process, review, and archive, and be accompanied by Form FDA 1571 ( USA-76 ) (cover sheet).

As per the G-IND-Safety and USA-38 , the submission must be identified as follows:

• “IND safety report” for 15-day reports
• “7-day IND safety report” for unexpected fatal or life-threatening suspected adverse reaction reports
• “Follow-up IND safety report” for follow-up information

The report must be submitted to the appropriate review division (i.e., Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) ). Per USA-38 , the FDA recommends that sponsors submit safety reports electronically. Other means of rapid communication to the respective review division’s Regulatory Project Manager (e.g., telephone, facsimile transmission, email) may also be used. Per USA-90 , fatality reports to CBER should be sent to [email protected] .

Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign suspected adverse reaction reports on CIOMS Form I (See USA-13 and USA-3 ) instead of Form FDA 3500A ( USA-75 ). See USA-38 and USA-48 for additional information.

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.

As per the US-ICH-GCPs , the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

As specified in 21CFR312 , the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56 and the US-ICH-GCPs the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

• Title, purpose, and description of patient population, and current status
• Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
• Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
• Description of the general investigational plan for the coming year
• Updated investigator’s brochure, if revised
• Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
• Brief summary of significant foreign marketing developments with the drug
• A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11 , trial updates must be submitted to ClinicalTrials.gov ( USA-78 ) according to the following guidelines:

• Not less than once every 12 months for updated general trial registration information
• Not later than 30 calendar days for any changes in overall recruitment status
• Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

As indicated in 21CFR312 , an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

The US-ICH-GCPs also states that upon the trial’s completion, the investigator should inform the institution and the investigator/institution should provide the EC with a summary of the trial’s outcome, and supply the FDA with any additional report(s) required of the investigator/institution.

Additionally, per 42CFR11 and USA-70 , the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to USA-78 that indicates either: 1) the FDA has not yet approved, licensed, or cleared the IP being studied for marketing; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year. The results information must include data on the following:

• Participant flow
• Demographic and baseline characteristics
• Outcomes and statistical analysis
• Adverse events
• The protocol and statistical analysis plan
• Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.

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 .

As per 21CFR312 , 21CFR50 , and the US-ICH-GCPs , a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312 , 21CFR50 , and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO).

Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. However, per the US-ICH-GCPs , although a sponsor may transfer all trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.

As indicated in 21CFR312 , a sponsor may be either domestic or foreign.

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.

As set forth in 21CFR312 and the US-ICH-GCPs , the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

• Signed investigator’s statement (Form FDA 1572 ( USA-77 ))
• Curriculum vitae
• Financial disclosure information

As addressed in the G-1572FAQs , Form FDA 1572 ( USA-77 ) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA) 's clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, prior to the start of the study, the sponsor must provide the investigator(s) with the protocol and the investigator’s brochure.

See G-InvstgtrResp for more information on investigator responsibilities.

As per the G-InvstgtrAdmin , the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

No information is currently available.

As per 21CFR50 and the G-DMCs , Data and Safety Monitoring Boards (DSMBs), (also known as a Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, as stated in 21CFR50 , the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation. See the G-DMCs for FDA recommendations on DSMB/DMC establishment.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-65 ), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72 , all National Institutes of Health (NIH) -funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS) /NIH requirements.

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a DSMB 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.

For all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section , the RevComRule , and G-CoopRes for additional information.

The US-ICH-GCPs indicates that in the event of a multicenter clinical trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and given EC approval
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication among investigators is facilitated

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

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.

The United States (US) regulations do not require insurance.

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).

According to the US-ICH-GCPs , the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

As specified in 21CFR50 , the Pre2018-ComRule , the RevComRule , and US-ICH-GCPs , for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

As per the FDA’s G-SbjctPayment , compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

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.

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.

Per the US-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. The quality management system should use a risk-based approach that includes:

• During protocol development, identify processes and data that are critical to ensure participant protection and the reliability of trial results
• Identify risks to critical trial processes and data
• Evaluate the identified risks, against existing risk controls
• Decide which risks to reduce and/or which risks to accept
• Document quality management activities and communicate to those involved in or affected by these activities
• Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, describe 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 US-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 US-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 all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per the G-ICH-E19 , the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the G-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research.

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-6 for information on the National Institutes of Health (NIH) ’s data management and sharing policy, the NIHDataMngmnt , which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data.

As part of its QA system, the US-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 US-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 auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with the sponsor’s 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).

The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
• Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA .

As delineated in 21CFR312 and the US-ICH-GCPs , if the sponsor determines the study presents an unreasonable and significant risk to the participants, the sponsor must discontinue the study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining drugs and provide the FDA with a full report on the sponsor’s actions.

According to the US-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 EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

The G-InfrmdCnsnt , which is the FDA’s discussion of the regulations in 21CFR50 , further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an investigational product (IP) that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow-up may be available or necessary.

21CFR312 indicates that if the FDA terminates an investigational new drug application (IND) based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

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.

Per the US-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 operating 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 US-ICH-GCPs for additional information.

As set forth in 21CFR312 and the US-ICH-GCPs , the sponsor must retain all sponsor-specific essential documents pertaining to the trial for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if a NDA is not approved, until two (2) years after shipment and delivery of the drug for investigational use is discontinued and the Food & Drug Administration (FDA) has been notified. The sponsor should also inform the investigator(s)/institution(s) in writing of the need for record retention and when the trial-related records are no longer needed. Additionally, per 21CFR312 , the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

In addition, the US-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.

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.

As stated in USA-86 , the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87 , the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164 ; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule ) and Food & Drug Administration (FDA) ( 21CFR50 and 21CFR56 ) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state level personal data protection requirements.)

Per the Privacy Rule, a covered entity means: a health plan; a health care clearinghouse; or a health care provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.

According to the FDA’s G-CertCnfdntlty , a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.

NIH Privacy Requirements

The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct , which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.

Per USA-86 , the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:

• Documented EC or privacy board approval
• Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
• Research on protected health information of decedents
• Limited data sets with a data use agreement
• Research use/disclosure with individual authorization
• Accounting for research disclosures

See USA-86 for more information on these circumstances.

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.

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

In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on agency-specific compliance.) Department of Health & Human Services (HHS) -funded or sponsored clinical trials must also comply with 45CFR46-B-E . The FDA has also adopted the US-ICH-GCPs as guidance.

As per 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-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) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND).

Per the G-RevComRule-FDA , the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule , which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved ICF used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12 , two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov ( USA-78 ) and a docket folder on Regulations.gov ( USA-79 ). According to the RevComRule , if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.

According to 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the investigator must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or the legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

As indicated in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , none of the oral and written information concerning the research study should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Additionally, per the RevComRule , participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens. See USA-54 and USA-60 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50 , the Pre2018-ComRule , and the RevComRule , the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or a legal representative(s) or guardian(s) to read before it is signed.

See the FDA’s G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.

See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50 . Also, see USA-54 and USA-60 for additional information regarding informed consent.

According to 21CFR50 , the US-ICH-GCPs , and the G-IRBFAQs , the EC should determine the need to re-consent enrolled participants in the event of an ICF modification due to protocol changes or new information which may, in turn, affect the willingness of already enrolled participants to continue in the study. The communication of this information should be documented.

The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.

21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or the legal representative(s) or guardian(s).

As delineated in the FDA’s G-InfrmdCnsnt , when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-InfrmdCnsnt and USA-63 for detailed information.

As set forth in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the participant and/or a legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant and/or a legal representative(s) or guardian(s). In addition, the RevComRule explicitly allows electronic signatures for consent documentation.

Per 21CFR50 , the Pre2018-ComRule , and the RevComRule , if the consent information is only presented orally using the short form, the participant and/or the legal representative(s) or guardian(s) must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant and/or the legal representative(s) or guardian(s). The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50 . The date consent was obtained should be recorded in this note.

According to the US-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 or the legal representative(s)/guardian(s)
• The participant or the legal representative(s)/guardian(s), has orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Per the US-ICH-GCPs , before participating in the study, the participant or the legal representative(s)/guardian(s) should receive a copy of the signed and dated ICF.

Per the Pre2018-ComRule and the RevComRule , the EC may waive the requirement to obtain a signed ICF if it finds any of the following:

• The ICF would risk a breach of confidentiality by linking the participant to the study
• The research presents minimal risk and involves no procedures for which written consent is required outside of the study

The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.

The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative(s)/guardian(s) with a written statement regarding the research.

In addition, the Pre2018-ComRule states that for an EC to approve a general waiver or alteration of consent, the EC must find that:

• The research involves no more than minimal risk
• The research could not practicably be carried out without the requested waiver or alteration
• If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format
• The waiver or alteration will not adversely affect the rights and welfare of the participants
• Whenever appropriate, the participant will be provided with additional pertinent information after participation

In the G-MinRiskWaiver , the FDA informs sponsors, investigators, and ECs that it does not intend to object to an EC waiving or altering informed consent requirements for certain minimal-risk, clinical investigations.

Furthermore, the Pre2018-ComRule , the RevComRule , and the G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.

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.

Based on 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• The study purpose, procedures, and expected duration of the trial
• Identification of any experimental procedures
• Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
• Any expected benefits to the participant
• Disclosure of appropriate alternative procedures that might be advantageous to the participant
• Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Contact information for relevant individuals to contact in the event of a trial-related injury
• That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
• Foreseeable circumstances under which the investigator may remove the participant without consent
• The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
• Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
• Approximate number of participants in the study

As per 21CFR50 , for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov , as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

In the G-InfrmdCnsnt , the FDA also recommends the consent document advise participants that data collected on them up until the point of their withdrawal from a study will remain part of the study database and may not be removed. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50 .

The RevComRule also requires the following statements to be included in the ICF:

• Whether research results will be disclosed to participants
• Whether or not the participant’s information or biospecimens will be used or distributed for future research
• That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit
• Whether biospecimens research may include whole genome sequencing

Compensation Disclosure

The FDA’s G-InfrmdCnsnt further states that if no compensation in the event of injury is available, the consent process should include a statement informing the participant. See the G-InfrmdCnsnt for an example statement.

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 [email protected]

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.

In accordance with 21CFR50 , 21CFR312 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , the United States’ (US) ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

As set forth in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , a potential participant and/or a legal representative(s) or guardian(s) must be informed that participation is voluntary, that the participant 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.

As delineated in 21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , a potential research participant and/or a legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

As per 21CFR50 , the Pre2018-ComRule , and the RevComRule , participants should be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained. Per the US-ICH-GCPs , all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. 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 RevComRule does allow the use of identifiable private information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for additional information on identifiable private information or biospecimens, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The G-InfrmdCnsnt , which is the Food & Drug Administration (FDA) ’s discussion of the regulations in 21CFR50 , delineates how data should be handled when an enrolled participant decides to withdraw from a trial. Data collected on participants up to the time of withdrawal from clinical investigations of drugs conducted under an investigational new drug application (IND) must remain in the study database to maintain the scientific validity of the research. The FDA recommends that participants be advised in the consent document that the data collected on them up until the point of their withdrawal will remain part of the study database and may not be removed. If a participant withdraws from the interventional portion of the clinical investigation but agrees to continued follow-up not addressed in the original consent document, the investigator must obtain the participant’s informed consent for this limited participation using an EC-approved consent document. If a participant withdraws from the interventional portion of a clinical investigation and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access the participant’s medical record or other confidential records that would require additional consent from the participant. However, such records may be accessed consistent with the original consent process, without additional consent, to obtain information collected prior to the participant’s withdrawal from the study. See the G-InfrmdCnsnt for additional information.

21CFR50 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs state that the research participant and/or a legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

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

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

21CFR50 , 21CFR56 , the US-ICH-GCPs , and the G-ICEmrgncyReqs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by life-threatening medical emergencies, public health emergencies, or military operations.

Medical Emergencies

As per the US-ICH-GCPs , in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or a legal representative(s) or guardian(s), or if an effective treatment is lacking but the investigational product (IP) 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 institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) 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.

Emergency Use Situation

21CFR56 describes emergency use as the use of a test article, such as an IP, on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain EC approval.

21CFR50 and the G-EmrgncyUse indicate that even in an emergency use situation, obtaining participant consent is required unless the investigator and a physician not participating in the trial certify in writing the following:

• The participant is confronted by a life-threatening situation
• Informed consent cannot be obtained due to an inability to communicate with the participant
• Time is insufficient to obtain consent from the participant’s legal representative(s) and/or guardian(s)
• No alternative methods of approved or generally recognized therapy are available

Per 21CFR50 and the G-EmrgncyUse , if immediate use of the IP is, in the investigator's opinion, required to preserve the participant’s life and time is not sufficient to obtain an independent physician’s determination prior to using the IP, the investigator’s determinations should be carried out. However, within five (5) working days following the use of the IP, the investigator’s decision must be reviewed and evaluated in writing by a physician not participating in the investigation. According to 21CFR50 , 21CFR56 , and the G-EmrgncyUse , the investigator must also notify the EC within five (5) working days.

21CFR56 , the G-EmrgncyUse , and the G-IRBFAQs further state that following emergency use of the IP, EC review and approval is required for any subsequent use of the IP.

Emergency Research

The G-ICEmrgncyReqs defines emergency research as a planned clinical investigation that requires prior written Food & Drug Administration (FDA) authorization to proceed, and involves participant(s) who are in a life-threatening situation for which available treatments or in vitro diagnostic tests are unproven or unsatisfactory.

21CFR50 and the G-ICEmrgncyReqs delineate that for emergency research, the EC may approve the investigation without requiring the consent of all the participants if the EC (with the concurrence of a licensed physician who is an EC member or EC consultant, and not otherwise participating in the investigation) finds and documents the following:

• The participants are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence is necessary to determine the safety and effectiveness of particular interventions
• Obtaining informed consent is not feasible because: (i) the participants will not be able to give their informed consent as a result of their medical condition; (ii) the intervention under investigation must be administered before consent from the participants’ legal representative(s) and/or guardian(s) is feasible; and (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation
• Participation in the research holds out the prospect of direct benefit to the participants
• The clinical investigation could not practicably be carried out without the waiver
• The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legal representative and/or guardian for each participant within that window of time and, if feasible, to asking them for consent within that window rather than proceeding without consent
• The EC has reviewed and approved informed consent procedures and an informed consent document consistent with 21CFR50
• Additional protections of the rights and welfare of the participants will be provided

See 21CFR50 and the G-ICEmrgncyReqs for more details.

USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative(s) and/or guardian(s), no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.

Military Operations

21CFR50 and 10USC55 indicate that in the case of IP administration to a member of the armed forces in connection with participation in a particular military operation, the requirement for the member’s prior consent may be waived only by the US President. The US President may grant the waiver only after determining, in writing, that obtaining consent is not feasible; is contrary to the best interests of the military personnel; or is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.

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.

As per 21CFR56 , the Pre2018-ComRule , the RevComRule , and the US-ICH-GCPs , in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

21CFR56 and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Per 21CFR56 and US-ICH-GCPs , other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations. The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

For more guidance documents related to vulnerable populations, see USA-64 .

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

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 .

As set forth in 21CFR50 and 45CFR46-B-E , children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the study will be conducted. USA-25 further states that the age of majority in most states is 18 and therefore for legal purposes, children are those individuals who have not reached the age of 18. See USA-25 for a table delineating the legal age of majority by state in the United States (US).

Per the Pre2018-ComRule and the RevComRule , children require additional safeguards to be included in any research study in order to protect their rights and welfare. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

As delineated in the US-ICH-GCPs , when the research participant is a minor, informed consent should be obtained from a legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and in terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.

For all clinical trials that do not involve greater than minimal risk, 21CFR50 and 45CFR46-B-E state that a study may only be conducted if adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s).

For all clinical trials that involve greater than minimal risk but present the prospect of direct benefit to the child, 21CFR50 and 45CFR46-B-E indicate that a study may only be conducted if the following applies:

• The risk is justified by the anticipated benefit to the child
• The anticipated benefit is greater than or equal to the available alternative approaches
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardians

For all clinical trials involving children/minors that involve greater than minimal risk and do not present the prospect of direct benefit to the child, but will likely result in increased knowledge about the child’s disorder or condition, 21CFR50 and the 45CFR46-B-E state that a study may only be conducted if the following applies:

• The risk is slightly greater than minimal
• The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social, or educational situation
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)

For all clinical trials that present a reasonable opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors but is not otherwise approvable per 21CFR50 and 45CFR46-B-E , a study may only be conducted if the following applies:

• The institutional ethics committee (EC) (institutional review board (IRB) in the US) finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and,
• The Commissioner of Food and Drugs consults with an expert panel and has an opportunity for public review and comment to determine that the investigation satisfies the conditions of one (1) of the other earlier described research types, or the following conditions are met: the investigation will be conducted in accordance with sound ethical principles and adequate provisions are made for soliciting the assent of children and the permission of their legal representative(s) or guardian(s)

Per the RevComRule , certain exemptions may apply to observational research involving children. See the RevComRule for details.

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11 and USA-60 . Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50 .

Per 21CFR50 and 45CFR46-B-E , when determining whether children/minors are capable of providing assent, the EC must consider their age, maturity, and psychological state. Assent from a child/minor is not necessary for proceeding with the clinical trial if the following applies:

• The capability of some or all of the children/minors is so limited that they cannot reasonably be consulted
• The trial presents a potential direct benefit that is important to the health or well-being of the children/minors and is only available through the investigation

Further, the EC may waive assent, even if the children/minors are capable of providing assent, if it finds and documents the following:

• Trial involves no more than minimal risk
• The waiver will not negatively affect the rights and welfare of the children/minors
• The trial could not be implemented without the waiver
• The children/minors will be given additional information after participation, whenever appropriate

When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented. 21CFR50 and 45CFR46-B-E do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:

• When there is greater than minimal risk to the child with no direct benefit to the child, but the study will likely result in increased knowledge about the child’s disorder or condition
• Research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors, but is not otherwise approvable

Exceptions to the two (2) legal representatives’ and/or guardians’ consent requirement are when one (1) legal representative or guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) legal representative or guardian has legal responsibility for the care and custody of the child.

The G-InfrmdCnsnt indicates that when obtaining legal representative or guardian permission, in the event that the legal representative(s) or guardian(s) of a child does not understand English, the permission must be obtained and documented in a language that is understandable to the legal representative(s) or guardian(s). The child who will be participating in the research should not be used as an interpreter for the legal representative(s) or guardian(s), even if the child is fluent in English and may be able to assent. Further, legal representative or guardian permission and child assent should be viewed as an ongoing process throughout the duration of a clinical investigation. If and when a child who was enrolled in a clinical investigation with legal representative or guardian permission reaches the legal age of consent, that participant no longer meets the definition of a child under 21CFR50 , and the investigator should obtain the participant’s informed consent prior to performing any further research interventions and/or procedures involving that participant. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50 .

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
• 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.

As per 21CFR50 and 45CFR46-B-E , for studies involving women of childbearing age or who are pregnant, a statement should be provided in the informed consent form (ICF) indicating that the treatment or procedure may involve risks to the participant, embryo, or fetus, which are currently unforeseeable. According to the US-ICH-GCPs , the ICF should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

Per the Pre2018-ComRule , pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare. Furthermore, according to the RevComRule , all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

All Department of Health & Human Services (HHS) -sponsored or -funded research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates must comply with Subpart B of 45CFR46-B-E .

Pregnant Women and Fetuses

As per 45CFR46-B-E , pregnant women and fetuses may participate in research if all of the following criteria are met:

• Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
• Risk to the fetus is caused solely by procedures that provide potential direct benefit to the woman or fetus. If there is no potential direct benefit, then the risk to the fetus cannot be greater than minimal, and the intent of the study is to develop important biomedical knowledge that cannot be obtained otherwise
• Least possible risk involved for achieving the research objectives
• Consent is obtained from the woman for studies that provide potential direct benefit to the pregnant woman and/or fetus, and studies with minimal risk to the fetus conducted to develop important biomedical knowledge that cannot be obtained otherwise
• Consent is obtained from the pregnant woman and the father if the study provides potential direct benefit solely to the fetus. Paternal consent is not required if the father is unavailable, incompetent, temporarily incapacitated, or the pregnancy was a result of incest or rape
• All individuals providing consent are fully informed about the foreseeable impact on the fetus or neonate
• No inducements will be offered to terminate a pregnancy
• Participants will not be involved in determining the timing, method, or procedures for terminating a pregnancy
• Participants will not be involved in determining the viability of a neonate

45CFR46-B-E states that neonates may not be involved in research unless all of the following criteria are met:

• All individuals providing consent are fully informed about the foreseeable impact on the neonate

Neonates of uncertain viability may not be involved in research unless the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the following additional conditions are met:

• Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise and there is no added risk resulting from the research
• Informed consent is obtained from either parent, or if neither parent is able to provide consent, then consent is obtained from the neonate’s legal representative and/or guardian. Paternal consent is not required if pregnancy was a result of incest or rape.

Nonviable neonates may not be involved in research unless the following additional conditions are met:

• Vital functions will not be maintained artificially
• Research will not terminate the heartbeat or respiration
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
• Consent is obtained from both parents. If neither parent is able to provide consent, informed consent of one (1) parent will suffice. Paternal consent is not required if pregnancy was a result of incest or rape. Consent of a legal representative or guardian of either or both parents will not suffice.

Viable neonates may only be included in research to the extent permitted by and in accordance with the RevComRule and subparts B and D of 45CFR46-B-E .

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.

21CFR56 , 45CFR46-B-E , and the US-ICH-GCPs include prisoners in their description of vulnerable populations. As set forth in 45CFR46-B-E , a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.

Per the Pre2018-ComRule and the RevComRule , prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare. As delineated in the RevComRule , none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

45CFR46-B-E states that prisoners may participate in biomedical or behavioral research conducted or supported by the Department of Health & Human Services (HHS) only if the following criteria are met:

• The institution conducting the research has certified to the HHS Secretary that the research has been approved by the institutional ethics committees (EC) (institutional review board (IRB) in the United States (US)); research involves minimal risk; and studies focus on the possible causes, effects, and processes of incarceration and criminal behavior, prisons as institutional structures, or prisoners as incarcerated persons
• Research should focus on conditions specifically affecting prisoners as a class, or practices that have the intent and likelihood of improving the health or well-being of participants only after the HHS Secretary has consulted the appropriate experts, and a Federal Register notice is published indicating intent to approve such research

See USA-62 for more HHS information on prisoner research.

As per 45CFR46-B-E , ECs have additional approval responsibilities when reviewing research studies involving prisoners. An EC must only approve these studies if it determines that:

• The research under review represents one (1) of the permissible categories of research delineated in Subpart C
• The prisoner’s judgement will not be impaired by any possible advantages accruing to the prisoner through participation in the research, when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison
• Research risks are commensurate with those that would be accepted by non-prisoner volunteers
• Procedures for participant selection within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners
• Information is presented in a language understandable to the prisoner population
• Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on parole
• As needed, adequate provisions have been made for follow-up examination or care of participants, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact

See Subpart C of 45CFR46-B-E for additional EC requirements related to prisoner research.

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.

In accordance with 21CFR56 , the Pre2018-ComRule , and the US-ICH-GCPs , an institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent. According to the G-InfrmdCnsnt , which is the Food & Drug Administration (FDA) ’s discussion of the regulations in 21CFR50 , impaired consent capacity may involve partial impairment, impairment that fluctuates over time, or complete impairment. Consent capacity can be affected by a wide range of disorders and conditions, such as dementia, stroke, traumatic brain injury, intellectual and developmental disabilities, serious mental illness, intoxication, and delirium.

Per the Pre2018-ComRule and the RevComRule , this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

USA-60 further indicates that while Department of Health & Human Services (HHS) regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

As stated in the FDA’s G-InfrmdCnsnt , ECs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Considerations that may help address these challenges and provide additional safeguards include:

• Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional

• Establishing a waiting period in the decision-making process to allow additional time for decision-making

• Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible

• Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire

• Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline

• Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes

• Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented

• Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time

• Determining whether the EC or a third party should observe the consent process

See the G-InfrmdCnsnt for additional information and FDA discussion of the regulations in 21CFR50 .

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.

As delineated in 21CFR312 , an investigational new drug is defined as a new drug or biological drug that is used in a clinical investigation. This includes a biological product that is used in vitro for diagnostic purposes. The terms ‘investigational drug’ and ‘investigational new drug’ are deemed to be synonymous for the purposes of this part.

Additionally, the US-ICH-GCPs defines an investigational product 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, or when used for an unapproved indication, or when used to gain further information about an approved use.

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.

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: [email protected] . 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 .

According to 21CFR312 and USA-42 , the Food & Drug Administration (FDA) is responsible for authorizing the manufacture of investigational products (IPs) (also known as investigational new drugs in the United States (US)).

Per 21CFR312 , sponsors that use an IP not already subject to a manufacturer’s investigational new drug application (IND) or marketing application are required to provide all of the technical chemistry, manufacturing, and control (CMC) information outlined in the application content and format requirements section of 21CFR312 , unless such information may be referenced from applicable scientific literature. Sponsors using an IP already subject to a manufacturer’s application should follow the same general application format but may, if authorized by the manufacturer, refer to the manufacturer’s application to provide the technical (CMC) information supporting the proposed clinical investigation.

Moreover, as stated in 21CFR312 , a sponsor may ship an IP to the investigators named in the IND under the following conditions:

• Thirty (30) days after the FDA receives the IND, or
• FDA provides earlier authorization to ship the IP

The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210 , the G-CGMP-Phase1 , and the G-INDPrep . The US-ICH-GCPs also states that the sponsor must ensure that the products are manufactured in accordance with GMPs.

As set forth in 21CFR312 , the FDA is also responsible for authorizing the import and export of IPs. An IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements:

• The IP consignee is the IND sponsor, or
• The consignee is a qualified investigator named in the IND, or
• The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP

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.

Investigator's Brochure

In accordance with 21CFR312 and the US-ICH-GCPs , the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational new drug(s)/investigational product(s) (IPs) obtained through the earlier research phases. The sponsor must also update the IB as significant new information becomes available.

As specified in 21CFR312 and the US-ICH-GCPs , the IB must provide coverage of the following areas (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• A brief description of the drug substance and the formulation, including the structural formula, if known
• A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans
• A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans
• A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies
• A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug
• Summary of data and guidance for the investigator

See 21CFR312 and the US-ICH-GCPs for detailed IB content guidelines.

For investigational new drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.120 of 21CFR312 for detailed requirements.

According to USA-39 , submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA) .

The US-ICH-GCPs state that the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

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
• 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.

Investigational new drug/investigational product (IP) labeling in the United States (US) must comply with the requirements set forth in Section 312.6 of 21CFR312 , which include the following:

• The immediate package of an IP intended for human use must bear a label with the following statement: “Caution: New Drug-Limited by Federal (or US) law to investigational use”
• The label or labeling of an IP must not bear any false or misleading statements and must not represent that the IP is safe or effective for the purposes for which it is being investigated

The appropriate Food & Drug Administration (FDA) Center Director may grant an exception or alternative to the requirements above for specific lots, batches, or other units of a human drug or biological product that is or will be included in the Strategic National Stockpile.

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

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.

As defined in the US-ICH-GCPs , the sponsor must supply the investigator(s)/institution(s) with the investigational new drug(s)/investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Per 21CFR312 , the US-ICH-GCPs , the G-CGMP-Phase1 , and the G-INDPrep , the sponsor must ensure the following (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• IP manufactured according to any applicable good manufacturing practices (GMPs)
• Acceptable storage temperatures, conditions, and times for the IP

Refer to the US-ICH-GCPs , the G-CGMP-Phase1 , and the G-INDPrep for detailed sponsor-related IP requirements.

According to 21CFR312 , the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. The sponsor is also required to maintain records showing financial interest paid to investigators. See 21CFR312 for more details.

As per 21CFR312 and the US-ICH-GCPs , the sponsor and the investigator(s) must retain the clinical investigation records and reports for two (2) years after a marketing application (known as a New Drug Application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the Food & Drug Administration (FDA) has been so notified.

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).

A specimen, referred to as patient specimen in 49CFR173 , is defined as human or animal material collected directly from humans or animals and transported for research, diagnosis, investigational activities, or disease treatment or prevention. Patient specimen includes excreta, secreta, blood and its components, tissue and tissue swabs, body parts, and specimens in transport media (e.g., transwabs, culture media, and blood culture bottles).

In addition, 42CFR73 defines specimen as samples of material from humans, animals, plants, or the environment or isolates or cultures from such samples for diagnosis, verification, or proficiency testing.

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.)

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.

The import and export of human specimens, also known as patient/diagnostic specimens/substances or human biological materials in the United States (US), is governed by several federal agencies working cooperatively to ensure the safe transport of these materials. These agencies include, but are not limited to, the Department of Transportation (DOT) ’s Pipeline and Hazardous Materials Safety Administration (PHMSA) , the Centers for Disease Control and Prevention (CDC) ’s Import Permit Program (IPP) , the Department of Health & Human Services (HHS) , the United States Postal Service (USPS) , and the International Air Transport Association (IATA) . The IATA has also adopted all of the hazardous materials requirements set forth in the Technical Instructions for the Safe Transport of Dangerous Goods by Air ( USA-10 ) published biannually by the United Nations (UN) ’ International Civil Aviation Organization (ICAO) .

Infectious Specimens

Per 49CFR173 , 42CFR73 , 42CFR71 , USA-21 , USA-4 , USA-11 , and USA-31 , DOT’s PHMSA, IATA, USPS, and CDC’s IPP refer to an infectious specimen/substance as a Division 6.2 material (Category A or Category B), or a select agent, etiologic agent, toxin, or a vector of human disease. The CDC’s IPP is specifically responsible for the importation of infectious specimens/substances/biological agents/vectors of human disease per 42CFR71 and for regulating the possession, use, and transfer of select agents and toxins per 42CFR73 . See 42CFR71 , 42CFR73 , USA-31 , and USA-73 for further information and permit applications for these import/transfer programs.

Additionally, the Department of Commerce (DOC) ’s Bureau of Industry and Security is responsible for regulating the export of a wide range of infectious specimens that may require a DOC license. Refer to the Commerce Control List (CCL) in 15CFR774 and USA-30 to determine if a DOC export permit is required for specific specimens.

According to 49CFR173 , USA-21 , and USA-4 , certain materials and specimens are exempt from the DOT’s PHMSA, IATA, and USPS requirements for import/export of infectious specimens. These include materials that do not contain infectious substances; non-infectious biological materials from humans, animals, or plants; and specimens for which there is a low probability that the sample is infectious. Exempt human or animal specimens are not subject to regulation as hazardous materials but are subject to specific packaging procedures that must be followed when shipped. Please refer to 49CFR173 , USA-21 , USA-4 , and USA-11 for detailed DOT, IATA, and USPS shipping instructions.

NIH Specimen Requirements

The HHS’ National Institutes of Health (NIH) researchers must also comply with all applicable federal and international air and ground transport laws and regulations. Researchers must also receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens to the NIH. Detailed instructions about how to proceed are outlined in USA-71 .

Per USA-2 , the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.

In accordance with the G-TCPS2 , prior to collecting, storing, or using a research participant’s biological specimen(s), consent from the participant and/or the legal representative(s) and review/approval from the institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) must be obtained. Specifically, consent is required from the following:

• The participant who will be donating biological materials, or an authorized third party on behalf of a participant who lacks capacity, taking into account any research directive that applies to the participant, or
• A deceased participant through a donation decision made prior to death, or by an authorized third party

In addition, the G-TCPS2 states that in order to seek participant consent to use the participant’s biological materials in research, the investigator (s) must provide the prospective participant or authorized third party with the following information:

• The type and amount of biological materials to be taken
• The manner in which biological materials will be taken, and the safety and invasiveness of the procedures
• The intended uses of the biological materials, including any commercial use
• The measures employed to protect the privacy of and minimize risks to participants
• The length of time the biological materials will be kept, how they will be preserved, location of storage (e.g., in Canada or outside Canada), and process for disposal, if applicable
• Any anticipated linkage of biological materials with information about the participant
• The plan for handling results and findings, including clinically relevant information and incidental findings
• The participant’s right to request the withdrawal of data or human biological materials, including any limitations on the feasibility of that withdrawal

Per CAN-35 , if there is a possibility of secondary future use of biological materials, researchers should consider describing this possibility in the consent form and obtaining permission from participants to retain their data or biological materials for future use. If consent for future use is not obtained initially then researchers may be required to obtain re-consent from individuals in the future. Researchers should be as specific as possible when describing the potential future uses. For example, if future uses include possible genetic or genomic studies, this must be stated. The EC may not approve future uses that are too open-ended or too dissimilar from the initial use. It is generally preferable to give participants the opportunity to opt out of future use. If this option is not provided, researchers should be prepared to explain their decision to the EC. When seeking consent, researchers may wish to give participants different options for how their samples or data can be used, to accommodate differences in comfort levels among participants. In rare cases, it may be possible to use identifiable information for secondary use without the consent of the participants who provided that information. While the possibility of an exception may exist, the EC generally expects that researchers will make every reasonable effort to seek the consent of participants. Thus, the best practice is for researchers to always obtain consent for future use at the time of initial recruitment if there is any possibility of secondary use of data or biological materials. Also see the G-TCPS2 for additional details on confidentiality, future use of information, broad consent for the storage of human biological materials for future unspecified research, biobanks, and stem cell consent.

As delineated in the G-IC-IVDs , the Food & Drug Administration (FDA) only provides informed consent guidance with respect to its regulations governing the informed consent requirement when human specimens are used for FDA-regulated in vitro diagnostic device investigations.

Informed consent requirements guiding Department of Health & Human Services (HHS) -conducted or -supported research on human research participants is regulated by the Pre2018-ComRule and 45CFR46-B-E .

Per the Pre2018-ComRule and the G-SpecimensResrch , the HHS views research involving human subject specimens as research involving human participants and subject to informed consent requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. The RevComRule further defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. See the Pre2018-ComRule , RevComRule , the G-SpecimensResrch , USA-2 , USA-9 , and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, as defined by the HHS’ National Institutes of Health (NIH) in USA-72 , research with specimens, cells, cell lines, or data involves human subjects when:

• The specimens, cells, or data must be or must have been obtained from individuals who are alive, and must be or must have been obtained by an investigator conducting research; and
• The investigator either must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals, or must be obtaining or have obtained individually identifiable private information.

See USA-72 for detailed frequently asked questions (FAQs) on this topic.

Per the Pre2018-ComRule , the RevComRule , and USA-2 , prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or a legal representative(s). See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The RevComRule requires the informed consent form to provide one (1) of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

• A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility
• A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
• A statement that the subject's biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit
• Whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen)

Furthermore, the RevComRule delineates the requirements of broad consent—an alternative consent process—for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. Broad consent requires that the following information be provided to the participant and/or the legal representative(s) or guardian(s):

• Certain basic elements from the normal consent process related to risks, benefits, confidentiality, voluntary statement, commercial profit, contact information, and whole genome sequencing elements
• Types of research that may be conducted
• A description of the information or biospecimens that might be used in future research, whether sharing might occur; and the types of institutions or researchers that might conduct research
• A description of the length of time that the information or biospecimens may be stored, maintained, and used
• A statement that participants will or will not be informed of the details of any specific research studies that might be subsequently conducted
• A statement that research results either will or will not be disclosed to participants
• An explanation of whom to contact for answers to questions about the subject's rights and about storage and use of the subject's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the research could not practicably be carried out without the information in that form. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information on broad consent and informed consent waivers.

The HHS’ G-StoredData-Tissues and USA-2 recommend that the following be included in informed consent documents for biospecimen collection:

• A clear description of the operation of the biospecimen resource including details such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen
• Conditions under which samples and data will be released to recipient investigators
• Procedures for protecting the privacy of human research participants and confidentiality of data
• Specific descriptions of the nature and purpose of the research
• Information about the consequences of DNA typing if human genetic research is anticipated

(See the Required Elements and Participant Rights sections for additional information on informed consent).

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Research Excellence at CIHR: Implementing CIHR's Research Excellence Framework

CIHR has many existing strategies, policies and practices that align with the definition of research excellence . However, CIHR recognizes that more work is required to value and incentivize a holistic and inclusive approach to research excellence.

Given this, operationalizing CIHR's Research Excellence Framework will involve new actions, starting with the activities outlined below. In keeping with the 'evergreen' principle, CIHR will employ a learning approach to monitor, evaluate and update both the Framework and its implementation. The following information will be updated cyclically to ensure transparency on the progress made.

• Establish an External Advisory Committee on Ethics to provide guidance that supports CIHR's commitment to ethics in health research and health research ethics. Completed
• Co-develop and publish minimal consent guidance for clinical trials. Anticipated to be published in 2025

Equity, Diversity, and Inclusion

• Continue to implement CIHR's commitments under the Tri-agency EDI Action Plan (2018–2025) , particularly as it relates to measures to increase equitable and inclusive access to granting agency funding opportunities. Ongoing
• Co-develop, publish, and implement a CIHR Accessibility and Systemic Ableism Action Plan towards improving accessibility and addressing systemic ableism in the health research funding system. To be published in 2024 Implementation to follow
• Co-develop, publish, and implement a CIHR Anti-Racism Action Plan towards addressing systemic racism in the health research funding system. Anticipated to be published in 2025 Implementation to follow
• Implement equalization in the Project Grant competition for individuals who self-identify as being a visible minority in Canada or a person with a disability. June 2024
• Continue implementing the Health Portfolio Sex and Gender Based Analysis Plus Policy to ensure all CIHR policies, services and programs are developed with consideration of intersectionality. Ongoing
• Develop an agency-wide policy for inclusion across the lifespan, to increase equity in CIHR-funded research. Timeline to be determined

Indigenous Knowledge

• Further implement the Institute of Indigenous Peoples' Health strategic plan. Timeline to be determined
• Implement actions recommended by the Institute of Indigenous Peoples' Health to address anti-Indigenous racism in the health research funding system. Timeline to be determined
• Implement payment of indirect costs for Indigenous scholars . Anticipated to be implemented in 2024
• Develop, publish, and implement a Tri-Agency Indigenous Citizenship and Membership Affirmation Policy and Directive that outlines a respectful and culturally safe system of affirmation of citizenship and membership for funding and positions dedicated to Indigenous Peoples. Anticipated to be published in 2024 Gradual implementation anticipated to begin in 2024

Patient-Oriented Research

• Undertake a Strategy for Patient-Oriented Research (SPOR) Strategy and Governance Refresh to renew the objectives for Canada's SPOR that builds on successes to date and lessons learned, while also reflecting evolving health system, community, partner, and patient priorities. Anticipated to be published in 2025
• Develop, publish, and implement a Patient-Oriented Research Action Plan to support the robust involvement of people with lived and living experience with health inequities across core areas of CIHR's programs. Timeline to be determined

Knowledge Mobilization

Develop, publish, and implement a new CIHR Knowledge Mobilization (KM) Framework and Action Plan to enhance the impact and return on investment of agency-funded research.

Example early actions:

• Host a dialogue focused on opportunities to formalize and strengthen a pan-Canadian evidence-support system
• Develop and launch a new recurring KM program (e.g., to catalyze research co-developed with knowledge users)

To be published in 2024 Implementation to follow

Open Science

• Develop, publish, and implement an updated Tri-Agency Open Access Policy to require immediate open access to publications. Anticipated to be published in 2025 Implementation to follow
• Continue implementing the Tri-Agency Research Data Management Policy (DMP) to require the inclusion of DMPs in all strategic funding opportunities and data deposit associated with agency-funded research publications. Ongoing
• Enhance guidance and expectations related to compliance with the FAIR (findable, accessible, interoperable, reusable) data principles. Timeline to be determined

Training, Mentorship and Sponsorship

• Co-develop, publish, and implement a Tri-Agency Training Strategy to deliver an equitable, accessible, and effective suite of scholarships and fellowships that help support and prepare a diverse population of students and post-doctoral researchers for careers requiring strong research skills in all sectors of society. Anticipated to be published in 2024 Implementation to follow
• Develop, publish, and implement a CIHR Training and Career Support Framework and Action Plan to support health-research specific needs across research career stages, transitions, and paths. Timeline to be determined

Responsible Research Assessment

CIHR will continue taking overarching measures to be at the leading edge of responsible research assessment through national and international partnerships and collaborations:

• Continue the implementation of principles related to the San Francisco Declaration on Research Assessment (DORA) to ensure alignment across program design and peer review practices. Ongoing
• Contribute as a core partner of the Research on Research Institute (RoRI) Phase 2, to shape international funder-driven projects focused on transforming research systems and cultures. This includes partnering on a project specific to changing the role of funders in responsible research assessment and developing a global observatory of emerging practices in this area. Ongoing
• Publish an updated bias in peer review module that provides reviewers with the knowledge and skills necessary to identify and mitigate bias that can affect the peer review process, with new content on systemic bias, intersectionality, and bias related to gender identity, race, disability, and sexual orientation, among others. Anticipated to be published in 2024
• Implement broad responsible research assessment practices through the consistent consideration of all key components of research excellence across CIHR funding opportunities. Ongoing
• Implement process changes to capture CV information in a narrative format to allow applicants to include important contextual information, and peer review to recognize diverse contributions, backgrounds, and careers rather than an overreliance on decontextualized metrics such as journal impact factor. Timeline to be determined, with pilots ongoing
• Implement research excellence champions to influence culture change within CIHR's peer review committees and by extension the broader research community. Timeline to be determined

• Research Ethics Committees

The Genesis and Development of Research Ethics Committees in Canada, 1960–1978

• October 2021
• European Journal for the History of Medicine and Health 78(2):330-352
• 78(2):330-352
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Research and scientific integrity policy

Table of contents

1. effective date, 3. authorities, 4. objectives and expected results, 5. application, 6. research and scientific integrity principles, 7.1. implementation, 7.2. fostering a culture of science integrity, 7.3. openness, transparency and timeliness, 7.4. public communication of research and scientific information, 7.5. dissemination of research and scientific findings, 7.6. contributions to the research and scientific community, 7.7. role of employees in science advice and evidence-informed decision-making, 7.8. responsible conduct of research and science, 7.9. monitoring and performance evaluation, president of the nrc, vice-presidents, directors general, directors, managers and supervisors, nrc employees who conduct research, science or related activities, 9. definitions, 10. enquiries.

The NRC and its employees are committed to serving Canada and pursuing excellence in research and innovation by meeting the highest standards for ethics and integrity.

Championed by the NRC Departmental Science Advisor and Chief Science Officer, the NRC Research and Scientific Integrity Policy was adapted from the Government of Canada Model policy on scientific integrity and builds upon the NRC Vision, Mission and Values and the NRC Code of Conduct .

1.1. This policy takes effect on December 12, 2018

2.1. This policy is issued pursuant to the August 9, 2018 Memoranda of Agreement between the National Research Council of Canada (NRC) and the Professional Institute of the Public Service of Canada (PIPSC) in Respect of Scientific Integrity. This policy applies to all the NRC employees and other people working for the NRC (as defined in Section 9).

3.1. This policy should be read in conjunction with the NRC Code of Conduct (2013) Footnote 1 , which includes the Values and Ethics Code for the Public Sector Footnote 2 as adopted April 2, 2012, the Directive on the Management of Communications Footnote 3 , the Public Servants Inventions Act Footnote 4 , the Copyright Act Footnote 5 , and the NRC Policy on Conflict of Interest and Post-Employment. Footnote 6

3.2. Where there is conflict or incompatibility between this Policy and legislation and/or a provision of any relevant collective agreement, the provisions of the legislation or relevant collective agreement take precedence.

3.3. Where there is conflict or incompatibility between this Policy and a mandatory Policy instrument of the Treasury Board and/or the NRC policy instruments (i.e. policy, directive or standard), the provisions of the Treasury Board mandatory Policy instrument and/or the NRC policy instruments take precedence.

3.4. Where there is conflict or incompatibility between this Policy and a voluntary Policy instrument of the Treasury Board and/or the NRC policy instruments (i.e. guidelines or tools), the provisions of this Policy take precedence.

3.5. The NRC will maintain a record of all instances of conflict or incompatibility between this Policy and legislation, collective agreements, or Treasury Board policy instruments and/or the NRC policy instruments, and submit this record as part of the performance evaluation as per s. 7.9 of this Policy.

3.6. In consultation with employees and their bargaining agents, the President of the NRC has authority to support research and scientific integrity by establishing relevant and applicable standards for the design, conduct, management, review and communication of research and science within the NRC. When appropriate, the President can assign this authority to the NRC Senior Ethics Officer.

The objectives of this Policy are to:

4.1. Foster a culture that supports and promotes research and scientific integrity in the design, conduct, management, review and communication of research, science, and related activities.

4.2. Increase public, employee, client, collaborator and stakeholder trust in the credibility and reliability of the NRC research and scientific activities.

4.3. Enhance national and international recognition of NRC research and science excellence, which optimizes the NRC's ability to create industrial, economic and social benefits for Canadians.

4.4. Set out expectations regarding the design, conduct, management, review and communication of research, science, and related activities.

4.5. Enhance employee understanding of the contributions of research and science to evidence-informed decision-making, as well as the role of managers, communication specialists, researchers and scientists in the development of government policy and advice.

The expected results of this Policy are that:

4.6. Employees involved in the design, conduct, management, review, use or communication of research, science, or related activities understand and conduct themselves in a manner consistent with the principles of research and scientific integrity.

4.7. The NRC is recognized by employees, stakeholders, clients, collaborators and the public for its research and science excellence and as a reliable and credible source of research and scientific information.

4.8. The NRC Employees are recognized nationally and internationally for their research excellence.

4.9. As appropriate and to the extent possible, allegations of breach of the principles of research and scientific integrity as defined in s. 6 are addressed through a fair, impartial, efficient, confidential and respectful process.

4.10. Employees understand and seek to enhance the contributions of research and science to science advice, government policy and evidence-informed decision-making.

5.1. This Policy applies to all the NRC employees and other people working for the NRC, as defined in s. 9.

The NRC recognizes that stakeholder trust in the research and scientific information provided by government depends upon the integrity of the process by which such information is produced, managed and communicated. So too does trust in the decision-making process that makes use of such information.

Furthermore, the NRC recognizes that all employees must uphold and conform to standards of excellence accepted by the wider research and scientific community.

To this end, in designing, conducting, managing, reviewing, using or communicating research, science and related activities, the NRC employees shall:

6.1. Ensure that all such activities are carried out in a manner that is consistent with all relevant and applicable standards of research and scientific excellence, research ethics, responsible research conduct including health, safety and environmental standards.

6.2. Ensure that the conduct of the NRC research and science and any research or scientific products, as well as any associated communications, are free from political, commercial, client, and stakeholder interference.

6.3. In the absence of clear and compelling reasons for limiting disclosure, ensure that research and scientific information produced by the NRC is made available to the public in a timely manner and in keeping with the Government of Canada's Directive on Open Government.

6.4. Accurately represent and appropriately acknowledge the contributions of both themselves and others to their research or scientific work.

6.5. Avoid conflicts of interest, and ensure that any real, potential or apparent conflict of interest is explicitly recognized, reported and appropriately managed.

6.6. Encourage discussion based on differing interpretations of research and scientific evidence as a legitimate and necessary part of the research and scientific processes and, where appropriate, ensure that these differences are made explicit and accurately represented.

6.7. Ensure that the significant and meaningful contribution of all employees to government programs, policies, regulations, and decision-making is acknowledged in official publications or communications, including the names and roles of those who made significant contributions to these products and activities.

6.8. Report any breach of these principles (i.e. a breach of scientific integrity) to their supervisor, manager or designated official.

7. Requirements

7.1.1. This Policy will be communicated to all employees by the President of the NRC, supported by the Secretary General and the Departmental Science Advisor.

7.1.2. The NRC will continue to develop and implement the additional procedures, policies, guidelines, tools, training and professional development opportunities necessary to support this Policy.

7.1.3. The NRC will ensure that clients, contractors and/or collaborators involved in, or providing services in support of, research, science or related activities are informed of this policy.

The NRC recognizes two complementary approaches to fostering a culture of research and scientific integrity. One focuses on instilling the virtues that underlie responsible conduct in research, science and related activities (s. 7.2.1). A second focuses on the procedure for bringing allegations of breaches forward, the investigation of these allegations, and the consequences of a finding that a breach has occurred (s. 7.2.2)

7.2.1. Science virtues

In accordance with relevant collective agreements:

7.2.1.1. The NRC recognizes the importance of research networking with national and international peers and active participation in the business and organization of relevant scientific and professional societies, which form an important part of ensuring employees understand and are held to the standards of their communities.

7.2.1.2. The NRC recognizes the importance of the virtues underlying research and scientific excellence, including intellectual curiosity and honesty, constructive skepticism, meticulousness, avoidance of bias, humility in the discovery and use of science evidence, and the limitations of scientific inquiry. To this end, it will ensure to support training, education and professional development opportunities that allow employees to further their understanding of, and appreciation for, these virtues.

7.2.1.3. The NRC will ensure to support training, education, and professional development opportunities to inform and educate employees about responsible conduct in research, research ethics, and the annotation, management and archiving of research and scientific data.

7.2.1.4. The NRC will encourage the development and implementation of a research and scientific integrity mentorship program for employees, whereby mentors exhibiting exemplary science virtues in their conduct and work are paired with more junior employees.

7.2.2. Breaches of research and scientific integrity

7.2.2.1. When an employee believes that there has been a breach of research and scientific integrity, the employee shall seek to resolve the issue in a fair and respectful manner in accordance with the NRC Directive on Breaches of Research and Scientific Integrity Footnote 7 . In such cases, employees at all levels are encouraged to discuss and resolve these matters with their immediate supervisor. They may also seek advice and support from other appropriate sources including the NRC Senior Ethics Officer and their bargaining agents.

7.2.2.2. The President of the NRC will appoint a NRC Senior Ethics Officer to address allegations of breaches of this Policy in accordance with the related NRC Directive on Breaches of Research and Scientific Integrity .

7.2.2.3. The NRC Senior Ethics Officer will ensure that alleged breaches of this Policy shall be promptly and thoroughly reviewed and investigated by the NRC.

7.2.2.4. The NRC will endeavour to protect personal information and otherwise provide safeguards to ensure that employees may bring forward, in good faith, allegations of breach of scientific integrity or participate in an investigation procedure without prejudice or fear of reprisal.

7.2.2.5. When NRC employees have information that could indicate a serious breach of the NRC Code of Conduct (2013) they can avail themselves of the procedures laid out in the Public Servants Disclosure Protection Act Footnote 8 . They may also seek advice and support from other appropriate sources including the NRC Senior Ethics Officer and their bargaining agents.

The NRC recognizes and understands the importance of openness and transparency about all elements of the research and scientific process as well as the timely release of scientific and research information. It nonetheless also recognizes that there may be legitimate and compelling reasons that may limit the disclosure or availability of research or scientific information to employees, stakeholders or the public.

7.3.1. This policy, as well as any associated policies, directives or guidelines, may be posted on the NRC's public website in permission-less downloadable form.

7.3.2. As the current policy and any associated policies, guidelines or tools are amended and revised, the NRC will maintain an annotated electronic archive of all such changes, with all archive elements available in permission-less downloadable form.

7.3.3. No NRC employee shall suppress, alter or otherwise impede the timely release of research or scientific information in the absence of clear and compelling reasons for doing so.

7.3.4. NRC employees shall ensure that research and scientific information (including that produced by contractors, grantees, or other partners who participate in, or assist with, the design, conduct, use or management of research, science or related activities) is produced and disseminated in a timely and transparent manner, in the absence of clear and compelling reasons for not doing so.

The NRC recognizes the right to freedom of expression by all employees on matters of research or science. It also recognizes the important role of all employees in communicating research and scientific information to the public.

Moreover, the NRC recognizes that all employees are subject to the NRC Code of Conduct (2013). The NRC and all employees further recognize the need for caution and prudence in the public communication of classified or sensitive business, scientific or research information, as well as existing legal constraints on information disclosure. Finally, the NRC recognizes that effective public communication requires certain skills, and that employees may have different degrees of comfort with public fora.

7.4.1. Employees shall have the right, and are encouraged, to speak about or otherwise express themselves on science and their research, without approval or pre-approval of managers, supervisors or other relevant personnel, and without being designated as an official spokesperson. In doing so, they must respect the relevant provisions of the Access to Information Act Footnote 9 , the Public Servants Inventions Act , any formal and informal confidentiality and intellectual property protection expectations of the NRC and its clients, and the NRC Code of Conduct (2013).

7.4.2. In any public communications, employees must be familiar with and respect any legal restrictions on information disclosure such as privacy rights, matters before the courts, and cabinet confidences. They must also respect the NRC Code of Conduct (2013), and the Access to Information Act . Unless explicit approval to do so has been given by supervisors or managers, classified or sensitive business, research or scientific information shall not be discussed in any public communication.

7.4.3. In the case of planned formal public communication events with sufficiently long lead times (e.g. public talks or lectures), employees should notify their supervisor/manager of the upcoming event and provide a copy of their communication material for information purposes only and without prejudice. Where a public communication relates to an invention, that public communication must follow the disposition of that invention under the Public Servants Inventions Act .

7.4.4. In the case of formal public communication events with short lead times (e.g. media interviews) that effectively preclude prior notification, employees should notify their supervisor/manager as soon as possible after the event for information purposes only and without prejudice.

7.4.5. Pursuant to s. 7.4.2 and 7.4.3, the NRC will ensure that employees are provided with guidelines consistent with relevant collective agreements and the Directive on the Management of Communications, to assist them in determining the types of public communications for which supervisor/manager notification is desirable or required, and the appropriate timing and form of any such notifications.

7.4.6. Employees are under no obligation to act as public NRC subject matter experts or appear in public fora, and may decline any such invitation or request without prejudice, unless explicitly given this task by management.

7.4.7. Any public communication which describes work conducted by employees must be reviewed and approved by them or their designates before publication or dissemination, and must acknowledge their contribution(s). In cases where an employee does not wish authorship and/or their contribution to be acknowledged, they should be consulted as to whether, in their view, the work is accurately described and findings interpreted appropriately.

7.4.8. Employees are encouraged to participate in media training provided by the NRC, but this is not a requirement for them to express themselves about science or their research.

7.4.9. Where an employee is speaking in the role of an official spokesperson, they must identify themselves by name and position and speak on the record for public attribution.

The NRC recognizes that communication among researchers and scientists is critical to the development of scientific and scholarly knowledge. Moreover the NRC recognizes that its employees are part of a global community of scientific and scholarly expertise, their contribution to which is critical to maintaining and enhancing the credibility and reputation of NRC experts, the reputation and credibility of the NRC, and the contribution of the NRC to the knowledge economy.

As with public communications, employees disseminating or communicating information through research or scientific media are subject to, and bound by, the Access to Information Act , the NRC Code of Conduct (2013) and must abide by the Directive on the Management of Communication where it does not conflict with the relevant collective agreements.

The following outlines the NRC principles and procedures for publication approval. Approval to publish will not be unreasonably withheld.

7.5.1. Drafts of NRC research or scientific publications authored by NRC employees shall be submitted to their manager or supervisor prior to formal submission, and discussed in a timely fashion.

7.5.2. If the submitted research or scientific publication does not contain explicit comments about or recommendations on federal statutory, regulatory or policy matters, approval of publication content by managers, supervisors or other relevant personnel is not required before submission for publication, communication or dissemination. In doing so, employees must respect the relevant provisions of the Access to Information Act , the Public Servants Inventions Act , the Copyright Act , any formal and informal confidentiality and intellectual property protection expectations of the NRC and its clients, and the NRC Code of Conduct (2013).

7.5.3. If the research or scientific publication contains explicit comments about or recommendations on federal statutory, regulatory or policy matters, approval of publication content by managers, supervisors or other relevant personnel is required before submission for publication, communication or dissemination.

7.5.4. For communications that do require approval, managers, supervisors or other relevant personnel may require revisions or editorial changes. In the event that approval is contingent upon incorporation of such revisions or changes, and the author(s) are not in agreement with the suggested changes, the work will not be attributed to the employee if the employee so requests. In the event that approval is withheld, the author(s) shall be so informed in writing of the reasons.

7.5.5. In support of Articles 7.5.2 -7.5.4 and in consultation with employees and their bargaining agents, the NRC will develop guidelines to assist employees, managers and supervisors in identifying and distinguishing communications that do/do not require manager or supervisor approval.

7.5.6. The responsible author(s) of any research or scientific communication must ensure that:

• Approval of all listed authors and contributors is obtained;
• All authors share responsibility for the work in question and are prepared to defend the aspects of the research in which they were directly involved;
• Authorship is discussed at the earliest possible phase of the research and issues are addressed well before the writing of a manuscript;
• The work in question is not a republication of original work except when the republication involves translation or dissemination to diverse audiences and is consistent with existing standards on republication, including, for example, the publication of reviews;
• All contributions to the work are appropriately acknowledged in a manner conforming to accepted standards of the relevant discipline(s) and publication(s);
• The NRC authors' federal affiliations are listed;
• The communication has been subjected to appropriate independent peer review and that technical and/or editorial changes that may result from this review have been addressed;
• Matters related to acknowledgements and official languages have been appropriately managed and administered;
• The possibility of publishing in Open Access journals for scientific and technical papers has been explored;
• They have exercised due diligence in ensuring that all issues related to the Public Servants Inventions Act , intellectual property and related matters have been resolved;
• They understand relevant terms and conditions for publication, including copyright and level of authority required for approvals.

Moreover, employees should seek credible and reputable outlets for academic publication that conform to established practices and standards of academic publishing, including particularly rigorous peer review practices.

7.5.7. In cases where the NRC employees have provided data or information to be used in a government document (e.g. a report, briefing note, etc.), management and those responsible for preparing the documents should consult with the employee(s) concerned to ensure that the data/information is used and interpreted appropriately.

The NRC recognizes that the participation of NRC employees in the global scholarly community depends upon domestic and international collaboration and partnerships. Such collaborations and partnerships provide important opportunities for NRC employees to leverage their expertise, knowledge and infrastructure in developing research and scientific knowledge to the benefit of Canadians.

To this end, the NRC will:

7.6.1. Encourage and facilitate domestic and international research or scientific collaborations and partnerships between NRC employees and the external research and development communities in universities and colleges; provincial, territorial or indigenous governments; industry and business; and civil society.

7.6.2. Make a reasonable effort to appropriately resource participation in relevant scientific and professional societies, working committees, conferences, workshops and symposia identified by employees as well as management.

7.6.3. Make a reasonable effort to ensure appropriate engagement or participation of employees in international science and research-based fora of which Canada is a formal member.

Furthermore:

7.6.4. The NRC encourages activities related to collaboration with the extramural research and development communities, including the appointment of NRC employees to adjunct professorships.

The NRC recognizes that employees have important roles to play in providing advice that informs federal programs, policy, regulations and law. Research and scientific findings are an important source of evidence that must be appropriately considered in evidence-informed decision-making.

Moreover, employees have an important role to play in providing advice not only on the research required to resolve today's issues, but also to identify emerging scientific and technical issues, research directions and opportunities.

To this end and in consultation with employees and their bargaining agents, the NRC will develop and deploy transparent and systematic mechanisms and procedures for:

7.7.1. Gathering, evaluating and incorporating scientific advice into the NRC and government-wide policy and regulatory decision-making process.

7.7.2. Engaging employees in the design, development, and evaluation of robust and resilient research programs that will be able to meet the research needs of the future.

7.7.3. Identifying and prioritizing areas of federal authority for which the current federal science or research capacity is inadequate or where federal investment in research and development is likely to provide substantial benefits to Canadians.

In addition, the NRC will:

7.7.4. Support the development of training and professional development opportunities devoted to the roles of science and research in developing evidence to support evidence-informed decision-making. Such opportunities may be made available to all employees who engage in, supervise, manage, support, review, use or report on research and scientific activities; analyze, curate or communicate data or information generated by these activities; and/or seek to use information derived from these activities in decision-making.

The NRC is committed to ensuring that the NRC's research and science conforms to the highest standards of responsible research and science conduct and shall strive to follow the relevant and applicable research practices honestly, accountably, openly and fairly in the development and dissemination of research and scientific knowledge.

7.8.1. Research and scientific integrity involves the application of concepts of transparency, openness, high quality work, avoidance of conflict of interest and ensuring high standards of impartiality and research ethics. Employees involved in science or research shall conform to the standards of responsible research. Such standards include, but are not limited to ensuring that:

• All research and scientific activities (including study design and implementation; recording, analyzing, and interpreting data; and in reporting and publishing data and findings) are conducted with the highest scientific rigour;
• Complete and accurate records of data, methodologies and findings, including graphs and images, are maintained in a manner consistent with policies, processes and best practices. This curation is essential to the verification and/or replication of the work by others;
• Referencing and, where applicable, obtaining permission for use of all published and unpublished work, including data, source material, methodologies, findings, and images as appropriate;
• Authorship consent is obtained, and that all those and only those who have made a substantial (conceptual and/or material) contribution to, and who accept responsibility for, the contents of the publication or document;
• Individuals, organizations or institutions who have sponsored and/or funded the research are appropriately described and acknowledged;
• All and only those individuals who have participated in the research are appropriately recognized and acknowledged;
• The contribution of those and only those who have contributed to research, including funders and sponsors, is appropriately described and acknowledged;
• Any real, perceived or potential conflict of interest is reported and appropriately managed;
• Information included in grant or award applications is accurate and complete, including information on partners, collaborators, co-applicants, and that their permission to be listed has been obtained;
• Research involving humans or animals conforms with the NRC Policy for research involving human participants Footnote 10 and NRC Animal Care Committee Policies and Procedures Manual including Tri-council principles and procedures as specified in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans Footnote 11 and the Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals Footnote 12 respectively.

7.8.2. Employees involved in science or research shall avoid breaches of responsible research conduct. Research misconduct does not include unintended error (experimental, analytical, and/or computational) or honest differences in interpretations or judgments of data. All types of scientific misconduct must be interpreted reasonably with a sense of what is customary in the relevant scientific and research community. Such breaches include, but are not limited to:

• Fabrication: Making up data, source material, methodologies or findings, including graphs and images;
• Falsification: Manipulating, changing, or omitting data, source material, methodologies or findings, including graphs and images, without acknowledgement and which results in inaccurate findings or conclusions;
• Destruction of research records: The destruction of one's own or another's research data or records specifically to avoid the detection of wrongdoing or in contravention of this or any other applicable policies and/or laws, regulations and professional or disciplinary standards;
• Plagiarism: Presenting and using another's published or unpublished work, including theories, concepts, data, source material, methodologies or findings, including graphs and images, as one's own, without appropriate referencing and without permission where required;
• Redundant publication or self-plagiarism: The re-publication of one's own previously published work or part thereof, including data, in any language, without adequate acknowledgment of the source, or adequate justification;
• Invalid authorship or contributions: Inaccurate attribution of authorship, including attribution of authorship to persons other than those who have made a substantial contribution to, and who accept responsibility for, the contents of a publication or document. Invalid authorship also includes the failure to acknowledge those who have made substantial contributions to the work in question;
• Peer review abuse: non-disclosure of conflict of interest, unfairly delaying a rival's publication;
• Mismanagement of conflict of interest: Failure to appropriately identify and address any real, potential or apparent conflict of interest;
• Misuse of research funds: Failure to comply with the prescribed funding conditions and requirements;
• Inaccurate grant and awards application: Providing incomplete, inaccurate or false information in a grant or award application or related document, such as a letter of support or a progress report;
• Inaccurate statement of collaborations. Listing of co-applicants, collaborators or partners without their agreement;
• Research Practice Misconduct: Research activities that are contrary to health, safety and environment policies and in violation of human participant protocols and laboratory animal protocols; and
• Subject of a formal allegation: Failure to inform the NRC of any formal allegation for research misconduct by another organization.

The NRC will annually review this and associated policies, guidelines or tools to ensure they remain relevant and seek employee and applicable bargaining agent input and feedback on the implementation of this Policy and provide performance indicators as practical.

7.9.1. In consultation with the Office of the Chief Science Advisor (OCSA) and NRC's employees and their bargaining agents, the NRC will design, develop and implement a monitoring plan for this Policy that will provide information on (a) the extent to which the policy has achieved its objectives (that is, policy performance); and (b) future policy and associated instrument (e.g. guidelines, directives, etc.) adjustments, modifications or changes likely to improve policy performance. Any such plan must have regard for other government initiatives or circumstances that may affect estimated performance independent of, or in concert with, the Policy.

7.9.2. Any plan developed under article 7.9.1 shall explicitly identify (a) the performance indicators that will be monitored; (b) how the data on these indicators will be collected, annotated and curated; (c) how performance baselines will be characterized; and (d) how changes from baseline will be estimated and evaluated.

7.9.3. A copy of all data and information collected as part of the monitoring plan will be forwarded annually to the Office of the Chief Science Advisor (OCSA), the NRC's Joint Consultation Committee and the Governance Committee for Implementation of Government-Wide Scientific Integrity Policy comprised of the Secretary of the Treasury Board, the Chief Science Advisor and the President of the Professional Institute of the Public Service of Canada.

8. Responsibilities

The President of the NRC and his/her delegates are responsible for fostering an environment that encourages excellence and integrity in research, science and related activities, and for promoting a culture of open communication where employees may disclose, in good faith, information concerning breaches of scientific integrity. The President, with the support of the Secretary General, is also responsible for:

• ensuring that this Policy is communicated to all employees;
• monitoring compliance with this Policy within the NRC and taking corrective action as needed;
• performance evaluation of this Policy; and
• providing an annual confirmation of the compliance and reporting with this Policy as requested by the Governance Committee for Implementation of Government-Wide Scientific Integrity Policy.

Vice-Presidents, Directors General, Directors, managers and supervisors are responsible for implementation of this Policy. Such responsibilities include:

• informing employees about this Policy and ensuring that they are aware of their rights and responsibilities and obligations under the Policy;
• ensuring compliance with this Policy, providing to employees information about the processes available to them if they wish to make an allegation under this Policy, and addressing all allegations of breach of scientific integrity that are brought to their attention or of which they are aware; and
• ensuring that employees are aware of professional development and training opportunities that may be available in support of this Policy.

Specific responsibilities will be articulated in procedures and guidelines that will be developed to support this Policy.

All NRC employees involved in the design, conduct, management, review, use, or communication of research, science or related activities, and all persons conducting research, science or related activities under the auspices of the NRC will have primary responsibility for:

• ensuring their behaviour and conduct conforms to the principles of scientific integrity;
• ensuring that they design, conduct, manage, review, use, or communicate research or science in a manner fully consistent with this Policy;
• reporting a suspected breach of scientific integrity as soon as possible; and
• participating in good faith in any inquiry or investigation conducted pursuant to this Policy and the NRC Directive on Breaches of Research and Scientific Integrity .

Alteration : (of a scientific or research work): any change in the form or content of a research or scientific work that may affect the interpretation of the work and/or its implications.

Authors : those who have made a substantial intellectual contribution to the research, at a minimum through direct participation in at least two of the following activities: conception of the research project; performance of the research; interpretation of the data; technical assistance, and writing of the manuscript. General supervision of the research group, data collection, critical reviews of the manuscript and funding of the research are not generally sufficient for authorship.

Breach : (of research and scientific integrity): failure to abide by any of the provisions described in s. 6 or s. 7 of this Policy.

Classified or sensitive research or scientific information : research or scientific information which would normally be considered to be exempt from disclosure under the Access to Information Act .

Clear and compelling reasons : (for withholding publication of scientific or research information): legitimate reasons include, but are not limited to: (a) disclosure of such information is exempt under the Access to Information Act or the Security of Information Act ; (b) technical or technological constraints, contractual obligations, copyright, and/or intellectual property protections, limit or prevent making the information available.

Client : any person, organization or institution, whether internal or external to government, who (1) receives research, scientific or technical services carried out by the NRC; or (2) is a recipient and/or user of intellectual property, data or information provided or licensed by the NRC.

Collaborator : any person, organization or institution, whether internal or external to government, with whom the NRC jointly conducts research or scientific work aimed at investigating a problem or area of mutual interest.

Communication (of science): science communication involves any exchange of scientific or research information (including research results and interpretations thereof, methods, protocols, data, and products) in any form, between or among employees and the consumers or users of this information, including the public, other scientists or researchers, other government employees, and clients.

Compelling evidence : evidence of sufficient strength to convince the decision-maker that it is likely that the claim for which the evidence is adduced is true.

Employee : to be interpreted broadly to cover all employees within the NRC, including supplementary workers and students, all of whom have a greater or lesser role to play in the scientific integrity procedures described in this Policy.

Intellectual Property : means proprietary and/or technical information and/or know-how, including of scientific and technical discoveries of any kind and in a form which is useful, or has the potential to be useful, and transferable and which may be protected under law by way, but not limited to, patents, trademarks, copyrights, industrial designs, integrated circuit topographies and trade secrets.

Interference : any action that alters or suppresses the work or the impartiality of an employee, as understood within the NRC Code of Conduct, including the expectation that they provide decision makers with all the information, analysis and advice they need, while striving to be open, candid and impartial. Interference also includes alteration or inappropriate suppression of research methodology and results or dissuasion of reporting of results by any party, including clients. With respect to work conducted for or with third parties such as clients or collaborators, it is acknowledged that the NRC may, so long as the integrity of the research is maintained, consult with, or take reasonable direction from, such third parties on research direction.

People who work for the NRC : are NRC employees, as well as, guest workers, as well as independent and volunteer visiting workers that are working within an NRC facility and are either: receiving compensation, other than salary, from the NRC or working on an NRC project.

President : as defined in the National Research Council Act.

Related activity : any activity that (a) supports science or research (e.g. laboratory operations and management; infrastructure (including information and communication infrastructure); (b) uses research or scientific information as an input (e.g. solicitation or preparation of science advice; evaluation of research or scientific evidence); (c) involves the curation, communication or archiving of scientific or research data or information.

Research : any undertaking intended to extend knowledge through a disciplined inquiry or systematic investigation. Footnote 13

Researcher/Scientist : employees primarily involved in the application of comprehensive knowledge in a field of science or engineering, for the achievement of one of the following primary objectives:

• the planning, conduct, and evaluation of research and development in support of the advancement of scientific or technical knowledge in the fields of science and engineering, the resolution of which involves technological uncertainty;
• the provision of scientific or technical advice both within and outside the NRC derived as a result of conducting personal research; or
• the management of projects in the fields of science or engineering.

Science : the pursuit and application of knowledge and understanding of the natural world through application of one or more elements of the scientific method. In the context of the current policy, it is understood to include both fundamental and applied natural, physical, biomedical and social science, as well as engineering and mathematics. Footnote 14

Scientific integrity : the condition resulting from adherence to concepts of transparency, openness, high quality work, avoidance of conflict of interest and ensuring high standards of impartiality and research ethics.

Suppression : (of a scientific or research work): the deliberate withholding of a scientific or research work, or any portion thereof, from publication or dissemination, in the absence of clear and compelling reasons for doing so.

Timely manner : within a time frame that is consistent with usual review and approval processes, and consistent with logistical and resource constraints. The NRC or external collaborators may impose reasonable embargo periods to respect the right of a principal investigator to first publication.

For further information on this policy, contact the NRC Corporate Secretariat .

NRC Code of Conduct (2013) .

Return to footnote 1

Values and Ethics Code for the Public Sector .

Return to footnote 2

Directive on the Management of Communications .

Return to footnote 3

Public Servants Inventions Act .

Return to footnote 4

Copyright Act .

Return to footnote 5

The NRC policy on conflict of interest .

Return to footnote 6

The NRC Directive on Breaches of Research and Scientific Integrity .

Return to footnote 7

Public Servants Disclosure Protection Act .

Return to footnote 8

Access to Information Ac .

Return to footnote 9

The NRC Policy for research involving human participants .

Return to footnote 10

Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans .

Return to footnote 11

Canadian Council on Animal Care Guide to the Care and Use of Experimental Animals , Vol. 1 (2 nd edition).

Return to footnote 12

Adopted from the 2008 Tri-Council definition of research .

Return to footnote 13

Adopted from the Science Council .

Return to footnote 14

Alternate format

• Research and Scientific Integrity Policy (PDF, 389 KB)

Related links

• Research and Scientific Integrity Policy Guidelines

From: National Research Council Canada

Statement from the NRC – continued support for clients and collaborators during COVID-19

Statement from the National Research Council of Canada – continued support for clients and collaborators during COVID-19

April 9, 2020 – Ottawa, Ontario – As Canada and the world continue to deal with the COVID-19 pandemic, the National Research Council's (NRC) top priority is to protect the health and safety of our employees, colleagues, and stakeholders while supporting clients and collaborators.  The NRC is committed to helping Canada and stakeholders during this time of need. We are prioritizing our pandemic response, mandated by the Prime Minister, to address urgent COVID-19 challenges and support Canadian businesses who are developing solutions. Please visit our website for more information and to contact us should you require our services.

In an effort to limit the spread of the virus, 90 percent of NRC staff have transitioned to teleworking. Employees who remain onsite are working on COVID-related programs, and performing critical tasks such as ensuring our buildings are secure, monitoring equipment and facilities, keeping systems running safely, and receiving essential shipments at loading docks on reduced hours.  The NRC remains committed to all of our clients and collaborators, therefore we will continue to carefully consider which facilities need to remain open and which projects are critical to support Canada and Canadians during this difficult time.

NRC representatives will be reaching out to clients and collaborators directly, to understand their challenges and how we can best support them. We also continue to be available to discuss future projects.

For questions about payment terms, clients and collaborators are invited to contact the NRC's account receivable team at 1-866-545-1195 or [email protected] .

Media Relations National Research Council of Canada 613-991-1431 1-855-282-1637 [email protected]

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Research Ethics.ca

Institutions / Organizations

• National Council on Ethics in Human Research (NCEHR)
• Interagency Panel on Research Ethics (PRE)
• Canadian Association of Research Ethics Boards (CAREB)
• Canadian Institutes of Health Research (CIHR) Ethics Office
• Canadian Bioethics Society

Key Documents

• Tri-Council Policy Statement (TCPS)
• Personal Information Protection and Electronic Documents Act (PIPEDA)
• Good Clinical Practice: Consolidated Guideline
• CIHR Guidelines for Health Research Involving Aboriginal People
• CIHR Best Practices for Protecting Privacy in Health Research
• Interim Tri-Agency Measures for Human Pluripotent Stem Cell Research
• “Bioethics for Clinicians 10: Research Ethics” (Weijer C, Dickens B, Meslin E.  Canadian Medical Association Journal 1997; 156: 1153-1157)
• “Bioethics for Clinicians 17: Conflict of interest in research, education and patient care” (Trudo Lemmens & Peter A. Singer, Canadian Medical Association Journal 1997; 156: 1153-1157)

Research Ethics in Canada: Brief Overview

Human subjects research in Canada is generally governed by a document known as the Tri-Council Policy Statement (TCPS) . “Tri-Council” is a reference to Canada’s three federal granting agencies, namely the Canadian Institutes of Health Research (CIHR) , the Social Sciences and Humanities Research Council (SSHRC) , and the Natural Sciences and Engineering Research Council (NSERC) . The TCPS was issued in 1998, with amendments made in 2000, 2002, and 2005. The TCPS guides the review of all research conducted at institutions funded by any of those 3 agencies (i.e., all Canadian universities and many hospitals) and is considered the minimal standard for the ethical review of research involving humans. The interpretation and enforcement of the principles found within the TCPS is left to universities and hospitals, most of which have “Research Ethics Boards” (REBs) whose job it is to review research proposals and monitor ongoing research to ensure compliance with the TCPS.

The TCPS has recently been revised and the newest edition will be available in early 2009. Some of the changes and updates reflect a need for the TCPS to better address issues in qualitative research and creative practices . Additional refinements to notions such as risk of harm, privacy and confidentiality, vulnerability, delegated review and continuing review of research have been proposed and significant public consultation has been carried out as part of the process of revision.

Some kinds of research (e.g., drug trials) must meet additional requirements (such as those set out in Health Canada’s Clinical Trials Regulations). Canadian REBs often seek guidance, in addition, from such influential international documents as the Declaration of Helsinki .

• The Research Ethics Blog

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