 This is the DeHousie Health Law Institute's Health Law Primers electronic module series. This module, which is broken down into two parts, provides an overview of the regulation of human biomedical research in Canada. I am Michael Haskus, a professor at the Schulich School of Law and School of Health Administration at DeHousie University. This module is not intended to serve as legal advice. It is for educational purposes only. This module will examine the regulation of human biomedical research in Canada. It will begin by addressing the need to distinguish research from clinical practice. Next, the documents that directly or indirectly regulate Canadian biomedical research will be outlined. With that as a backdrop, the procedural and substantive aspects of the research ethics review process established by these instruments are then discussed. The module will end with a few concluding remarks. It is important to distinguish human biomedical research from clinical practice. This is sometimes difficult to do because research and clinical practice frequently occur in conjunction, since many medical interventions are delivered by physician researchers and form the subject of formal research projects into the intervention's safety and efficacy. Despite this difficulty, it is necessary to make this distinction because the application or non-application of regulatory instruments can turn on whether an activity is considered clinical practice or research. In the context of this module, research will be defined as an undertaking intended to extend knowledge through a disciplined inquiry or systematic investigation. This is the definition that is used in a document that plays a central role in the regulation of biomedical research in Canada. Namely, the Tri-Council Policy Statement Ethical Conduct for Research Involving Humans, which I'll refer to in this module by the abbreviation TCPS. The Canadian regulatory landscape for biomedical research involving humans consists of a complex patchwork of diverse forms of regulatory instruments. Let's have a look at some of these instruments. The first instrument we will look at is the TCPS. It establishes an ethical framework for the conduct of human participant research, including studies involving living human participants and research involving human biological materials, whether or not this material is derived from living or deceased persons. It also addresses research involving identifiable personal information collected from participants through various means such as interviews, questionnaires, and access to health records. The TCPS requires research institutions to establish or appoint multidisciplinary research ethics boards, which I'll refer to as REBS, to review and make decisions about the ethical acceptability of research involving humans that takes place within the institution's jurisdiction or under its auspices. These boards are empowered to approve, propose modifications to, or reject proposed studies. REBS may also require ongoing studies to be altered or terminated. If a particular activity meets a definition of research that we looked at earlier, this activity may be captured by the TCPS. If not, the TCPS does not apply to it. However, even if the activity constitutes research under that definition, it does not necessarily follow that the TCPS will apply. Being a policy statement, the TCPS lacks the inherent legal authority of legislation. On the other hand, the scope and extent of its regulatory impact rests on other factors. One such factor is that in order to be eligible to receive and administer funding from the tri-agencies, institutions must agree to abide by the TCPS. Additionally, the tri-agencies grant applications require applicant researchers to certify compliance with the TCPS. As a result, tri-agency funded researchers and their institutions must comply with the TCPS. The regulatory impact of the TCPS is not necessarily dependent on the presence of public funding for research. Members of some professional organizations may be required to seek ethics review of the TCPS-compliant REB before conducting human research or risk being subject to disciplinary action by their regulatory bodies. For instance, the College of Physicians and Surgeons of Alberta requires that this be done. There is also legislation that requires researchers to have their projects approved by TCPS-compliant REBs. This is required under Nova Scotia's Personal Health Information Act and Newfoundland and Labrador's Health Research Ethics Authority Act. In addition to the circumstances already outlined, other factors may serve to promote compliance with the TCPS. Ethics review of the kind provided for in the TCPS is often a condition of publication in peer-reviewed journals. As well, courts may invoke non-legal instruments such as the TCPS when determining the common law liability of researchers, REB members, and research institutions in tort actions arising from personal injuries. Now, let me talk a bit about a couple of documents that regulate drug research in Canada. The first is Part C, Division 5 of the Food and Drug Regulations, which I'll refer to as the Clinical Drug Trial Regulations. And the second document is the Good Clinical Practice Consolidated Guidelines, more commonly referred to as the GCP Guidelines. The Clinical Trial Regulations, passed pursuant to the Federal Food and Drugs Act, established legal requirements concerning the conduct of clinical drug trials. This slide sets out the definition of a clinical trial contained in these regulations. The Clinical Trial Regulations apply to all clinical trials in Canada, irrespective of how this research is being funded. The sponsor of the clinical trial must obtain approval of the REB at each clinical trial site. The REB must attest that it reviewed and approved the protocol and informed consent forms, and that it carries out its functions in a manner consistent with good clinical practices. The term good clinical practices is defined on the present slide. Health Canada has endorsed the principles and practices provided for in the GCP Guidelines. These international guidelines were developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The GCP Guidelines provide greater detail than the clinical trial regulations respecting the duties and responsibilities of REBs, investigators, and sponsors. And, to some degree, reflect the substantive and procedural norms in the TCPS. There are also relevant international documents. The growing involvement of Canadian researchers in multinational health research requires these researchers to familiarize themselves with the relevant regulatory frameworks adopted by other countries. The United States is one such country. In the US, the Code of Federal Regulations establishes legal standards for the protection of human research participants that apply to research funded by the United States Department of Health and Human Services, abbreviated DHHS. Other parts of the Code of Federal Regulations fall under the auspices of the United States Food and Drug Administration. And they apply to human research that uses drugs, medical devices, and biological products, regardless of whether the research is federally funded. A multitude of other federal and state laws may also be relevant depending on the research activities being pursued. These US regulatory instruments are relevant to Canadian researchers who carry out research supported by DHHS funding. Since the research must comply with the Code of Federal Regulations, even if the research is conducted outside the United States. Two international documents, the Nuremberg Code and the Declaration of Helsinki, have played a fundamental role in the formulation and evolution of international, regional, and national regulatory instruments for the protection of human research participants. They have expressly shaped other important international instruments, such as the international ethical guidelines for biomedical research involving human subjects, prepared by the Council for International Organizations of Medical Sciences in collaboration with the World Health Organization. The regulatory instruments I have described in the last few minutes are by no means the only instruments that impact the conduct of human biomedical research. The present slide mentions some additional regulatory instruments. Having had a quick look at some of the principal regulatory instruments for human biomedical research, we now turn our attention to the research review process that many of these instruments rely on. REBS are the workhorses of the governance regime. REBS are charged with a number of roles and responsibilities. The principal mandate of REBS is to approve the initiation of and conduct periodic reviews of biomedical research involving human subjects in order to ensure the protection of their rights, safety, and well-being. Our discussion of REBS is divided into two sections. The first section will focus on procedural features of research ethics review. Procedural matters include the process of research review, including the way in which REBS function as a committee and how research proposals make their way through the review process. The second section will examine some of the substantive aspects of the review. By this I mean the principles or criteria used by REBS to assess the ethical acceptability of research protocols. So let's begin our examination of the procedural aspects of REBS by looking at who sits on these boards. The regulatory instruments typically set parameters around the number of REBS members and they set the kinds of backgrounds and expertise the REBS membership needs to collectively possess. The TCPS requires that, for biomedical research, a REBS must consist of at least five members, including both men and women, of whom at least two members have expertise in relevant research disciplines, fields, and methodologies covered by the REBS. At least one member who is knowledgeable in ethics, another who is knowledgeable in the relevant law, and at least one community member who has no affiliation with the institution. The stated rationale for this membership requirement is to ensure the necessary basic background, expertise, and perspectives to allow informed independent reflection and decision making on the ethics of research involving humans. Prior to participant recruitment, access to data, or the collection of human biological material, researchers must have their research proposals, including pilot studies, approved by the relevant REBS. Therefore, the researcher will need to identify the REBS or REBS from which he or she will need to seek approval. The application or submission materials that researchers must provide to REBS can vary according to the specific demands of the relevant REBS and the particular type of research being proposed. The required documentation can include research summaries, consent forms, participant recruitment tools, questionnaires, interview guides, contracts entered into with sponsors, including confidentiality agreements, and the researchers curriculum fee type. What types of reviews do REBS conduct? The TCPS puts forward two levels of REBS review, full board review and delegated review. Full board review is the default requirement on the TCPS. That is, unless it is appropriate to proceed by way of delegated review, a full board review is necessary. Under the TCPS, full board reviews normally involve regularly scheduled, face-to-face REBS meetings during which each research project before the REBS is discussed with the aim of reaching a decision as to whether to approve, reject, or propose modifications to proposed research, or to terminate any ongoing research. On completing its discussion of a research proposal, the REBS must reach a reasoned, well-documented decision in accordance with the decision-making process that it has adopted. Delegated review usually involves the REBS delegating the research ethics review to one or more members of the REBS. In practice, this may well mean that those conducting the delegated review will not possess the full range of expertise and experience that exists within the REBS as a whole. Pursuant to the TCPS, decisions about the level of review required for particular study are to be made in accordance with the concept of proportionate review. This requires consideration of the level of foreseeable risks to participants. The lower the level of risk, the lower the level of scrutiny. The lowest level of scrutiny, of course, being a delegated review. On the other hand, the higher the level of risk, the higher the level of scrutiny, which will ultimately call for a full board review. If the research involves no more than minimal risk, it should normally receive delegated review, whereas above minimal risk research shall receive full board review. This raises the question of what constitutes, quote-unquote, minimal risk. Minimal risk research is defined as research in which the probability and magnitude of possible harms implied by participation in research is no greater than those encountered by participants in those aspects of their everyday life that relate to the research. In the context of biomedical research, any risk of harm that participants would have been exposed to as a consequence of undergoing medical treatment, irrespective of their participation in the study, is not considered in the minimal risk calculus. However, those interventions that serve only the needs of the study are included. The TCPS identifies several potential categories of harm that need to be considered in terms of their probability and magnitude. These include physical, psychological, behavioral, social, and economic harms. This slide provides some examples contained in the TCPS of research that may qualify for delegated review. Delegated reviews are inappropriate for clinical drug trials, with the possible exception of minor changes in ongoing trials. Once a research project has received REB approval and is underway, there is a continuing need to safeguard research participants. Researchers are required to report to the REB any unanticipated issue or event that may increase the level of risk to participants, or has other ethical implications that may affect participants' welfare. In its chapter on clinical trials, the TCPS requires researchers to promptly report new information that may affect the welfare or consent of participants to the REB and to others. Furthermore, researchers must promptly inform all participants to whom the information applies, and this includes former participants. This concludes Part 1 of the module. I will see you at Part 2, which deals with the substantive aspects of research ethics review. Before I leave you, I want to quickly thank the Dehousey Health Law Institute for generously supporting the development of this module. Thank you so much for your attention.