 This is the DeHousey Health Law Institute's Health Law Primer's electronic module series. This is the second part of the Regulation of Human Biomedical Research module. I am Michael Hatskis, a professor at the Schulich School of Law and School of Health Administration at DeHousey University. This module is not intended to serve as legal advice. It is for educational purposes only. You will recall that in Part 1 of the module, we looked at the distinction between research and clinical practice. We then explored some of the key regulatory instruments, and lastly, we examined the procedural aspects of research ethics review. In Part 2 of the module, we will explore the substantive aspects of research ethics review. After this, I will make a few concluding remarks. After being presented with the information pertaining to a particular research project through the ethics review process, TCPS-compliant REBs must deliberate on a large number of substantive issues. Regarding applications for approval of a proposed study, these issues are many. Some of them are set out in the present slide. The GCP guidelines also set out substantive norms that are to inform REB decision-making. These are largely consistent with the considerations set out in the TCPS. Substantive issues related to consent, privacy and confidentiality, and conflicts of interest in the part of researchers will form the focus of this section of the module. Consent is an essential aspect of the substantive review. In order for consent to participate in research to be legally and ethically valid, three conditions must be satisfied. First, the consent must be informed. Second, the consent must be voluntarily given. And third, the person giving consent must possess decisional capacity. I'll say a few words about each. I'll first deal with the requirements for consent to be informed. The Saskatchewan Court of Appeal case of Halushka vs. University of Saskatchewan is one of two influential judicial decisions in Canada on the issue of informed consent in biomedical research. In this case, a University of Saskatchewan student participated in the study that was intended to investigate individuals' circulatory response while under general anesthesia. During the consent process, the student participant was told a catheter would be inserted into a vein in his left arm and that he would receive a new anesthetic agent. He was also told that this was a safe test and there was nothing to worry about. The student then underwent the research interventions but experienced complete cardiac arrest that was caused by the agent. The court found the researchers' consent process to be negligent. In terms of the researchers' disclosure obligation, the court stated that the duty imposed upon those engaged in medical research to those who offer themselves as subjects for experimentation is at least as great if not greater than the duty owed by the ordinary physician or surgeon to his patient. The court also noted that a subject is entitled to a full and frank disclosure of all the facts, probabilities, and opinions which a reasonable person might be expected to consider before giving his or her consent. In the second influential case in Canada, Weiss vs. Solomon, the Quebec Superior Court was called upon to decide whether a recruiting physician, a physician researcher, the hospital in which the two worked, and a hospital's REB bore legal liability in connection with the death of a research participant named Weiss during an eye drop study that involved the use of fluorescein angiography. Soon after receiving the fluorescein injection, Weiss suffered cardiac failure and died as a result of an allergic reaction to the injection. The Quebec Superior Court found that Weiss's cardiac failure was an adverse reaction to the fluorescein injection and that he had not been informed of the slight risk of cardiac arrest from such injections. The hospital threw its REB and the researcher were held liable in negligence for the failure to properly inform Weiss. The court stated that the duty to inform in research involving no anticipated health benefits to participants is the most exacting possible. All risks must be disclosed, even those that are rare or remote, especially if they entail serious consequences. The TCPS and GCP guidelines also set out general disclosure standards. For instance, the TCPS states that researchers shall provide to prospective participants or authorize their priorities full disclosure of all information necessary for making an informed decision to participate in a research project. The GCP guidelines and the TCPS list in some detail information that is to be disclosed to participants during the consent process. The present slide lists some of the information that has to be disclosed. Before leaving the topic of informed consent, a couple of additional matters should be emphasized. Researchers' obligations extend beyond merely disclosing information to participants and other subsequent decision makers. They must also take steps to ensure the person giving consent understands and appreciates the information provided. The informed consent process must not be rushed or treated as a perfunctory routine. Potential participants must be given the opportunity to ask questions and be provided with ample time to contemplate whether they want to participate. Furthermore, the language used during the process, both oral and written, should be straightforward, devoid of technical jargon, and fixed at an appropriate comprehension level for the participants. This is something that many researchers fail to achieve. Not only must consent be informed, but it must also be given voluntarily. The TCPS and the GCB guidelines highlight this requirement. According to the TCPS, consent cannot be considered voluntary if it was coerced. Unduly influenced or given as a result of an excessive incentive. The TCPS states that coercion involves a threat of harm or punishment for failure to participate. Much attention has been dedicated to undue influence in the various forms it can take. The TCPS speaks of undue influence in terms of the impact that power relationships can have on prospective participants. This concern arises where researchers exercise or appear to exercise control over their prospective participants, leading the participants to feel compelled to abide the wishes of the researchers. For instance, prisoners and civilly committed persons are markedly dependent on persons and authority within the custodial institution, and therefore are ripe for being unduly influenced to participate in research. Concerns about voluntariness are extremely acute when the consent of desperately ill patients is being sought in relation to studies, usually drug trials, that hold the last hope of rescue. Incentives, monetary or otherwise, are often used to encourage participation in a research project. They can however undermine the voluntariness of participants. Consent. The TCPS indicates that where incentives are used, they should not be so large or attractive as to encourage reckless disregard of risks. It also places the onus on researchers to justify their proposed incentive plans to the Rev. This brings us to the third aspect of consent. The person giving consent to research participation must have the capacity to make this decision. Serious ethical issues arise when persons with diminished decisional capacity are involved in research. The incomplete cognitive development that exists during various phases of childhood, the impact of mind altering substances, or the presence of a disorder that results in temporary or permanent cognitive impairment may account for a research participant's diminished capacity. According to the TCPS, in order to be considered to have decisional capacity, individuals must possess two distinct competencies. One, the ability to understand the relevant information about the specific study, and two, the ability to appreciate the potential consequences of making a decision to participate or not participate in the study. The first competency involves the cognitive ability of participants to process and retain information about matters relevant to participation, such as the potential harms and benefits that might be occasioned if they are enrolled in the study. The second calls for the ability to evaluate the information about the study that they have acquired. This demands the ability to apply the relevant information to a person's individual circumstances and to weigh the consequences of participating or not participating. Competence should not be viewed as being global or static. An individual may have the capacity to consent to participate in one study. For example, the completion of a questionnaire that elicits nonsensitive information but not able to consent to another. That might be a clinical trial involving a new chemotherapy agent. Moreover, a particular person's ability to consent to participate in a study may fluctuate even over short-time intervals. Competent adults can legally consent to participate in research and be irrespective of whether it holds any potential benefits for them. However, the situation is not as clear for minors. In the minors and the law module, you learned about the common law mature minor principle in the context of medical treatment decisions. If a minor is sufficiently mature, the minor has the capacity to make a decision regarding the medical treatment he or she will accept or reject. While it is unclear whether the common law mature minor principle applies to minors' decisions regarding research participation because no court has been asked to rule on this matter, the courts may hold that it does. What about situations where a minor or adult lacks decisional capacity? In this context, significant ethical and legal issues arise when considering whether such persons can be enrolled in a specific study, including only competent participants in research can unduly exclude certain groups, such as children and persons with mental disabilities, from the benefits of research. Thus, automatic exclusion of prospective research subjects based on mental disability is inconsistent with the TCPS or conceptions of distributive justice, inclusiveness, and equality. However, there are ethical and legal restrictions on the inclusion of persons lacking capacity in research. The TCPS and GCP guidelines state that persons lacking capacity cannot be enrolled in research unless certain conditions are met. Both instruments require the research question can only be addressed with participants within the identified group. If competent persons would make equally fitting participants for a given study, incompetent persons cannot be enrolled. The TCPS and GCP guidelines also require that consent be sought and maintained from authorized third parties. Where incompetent minors are involved, the legally authorized third parties are the minors' parents or legal guardians. Additionally, under the TCPS and GCP guidelines, research cannot expose persons who are incompetent to more than minimal risks without the potential for direct benefits for them. The TCPS also states that, where the research entails only minimal risk, it should at least have the prospect of providing benefits to participants or to a group that is the focus of the research and to which the participants belong, and that participants can only be exposed to minimal burden. It does not necessarily follow from the determination of incapacity that the person lacking capacity cannot take part in the decision to participate in research. Indeed, Article 3.10 of the TCPS requires researchers to ascertain the wishes of the individual who lacks legal capacity if that person has some ability to understand the significance of the research. If such a person descends, his or her participation is precluded. The substantive review of research by REBS also includes considering issues of privacy and confidentiality. The TCPS has an entire chapter on privacy and confidentiality that, in its opening article, states the following general duty. Researchers shall safeguard information entrusted to them and not misuse or wrongfully disclose it. Institutions shall support their researchers in maintaining promises of confidentiality. Subsequent articles elaborate on this duty. Researchers must advise the REBS and inform participants during the consent process about how they will comply with confidentiality obligations and must explain to the REBS and participants any reasonably foreseeable disclosure requirements, which, depending on the nature of the biomedical research project, might include mandatory reporting of suspected child abuse to child welfare agencies pursuant to provincial child welfare legislation and reporting of certain suspected communicable diseases to public health officials under public health legislation. Care must also be taken to ensure that participants are advised of the possibility of disclosure of their personal information to other individuals or groups, such as research sponsors and REBS. The TCPS obligates researchers to provide REBS with details concerning their proposed measures for safeguarding information and it provides REBS with factors for assessing the adequacy of these proposed measures. There are many significant privacy issues that serve us in biomedical research. For instance, data linkage studies, which are now blossoming as society becomes fully ensconced in an electronic era, can raise the prospect of re-identification of individuals when de-identified or anonymized databases are brought together. The TCPS addresses this issue in Article 5.7. The storage and banking of human biological materials is another area that implicates privacy issues and which is addressed by the TCPS. Researchers must be aware of privacy-related responsibilities. These responsibilities include, among other things, being aware of all applicable policies and laws and the jurisdictions in which the research is conducted and conducting their research in accordance with such requirements. For example, legislation devoted to the subject of personal health information exists in many provinces, including Nova Scotia, and this legislation has specific provisions regarding research. The sheer breadth and complexity of the potentially relevant regulatory instruments makes this a very tall order. RevReview is also concerned with potential conflicts of interest on the part of researchers. The presence of a conflict of interest in the research setting can undermine the trust relationship between researchers and research participants, research sponsors, research institutions, and the public. The interests of research participants and researchers can coincide or conflict. The expanding body of literature devoted to exposing the negative impacts of the commercialization of biomedical research on researchers' design and conduct of studies, as well as study results, offers a bountiful supply of examples of clashing interests. The clinical trial regulations and the GCP guidelines are almost entirely silent on the issue of conflicts of interest. However, Revs and researchers that govern their affairs according to the TCPS are given some direction on this issue. Chapter 7 of the TCPS is committed to the topic of conflicts of interest. The TCPS requires researchers to disclose in research proposals they submit to the Rev any real, potential, or perceived individual conflicts of interest, as well as any institutional conflicts of interest of which they are aware that may have an impact on their research. The TCPS mentions some situations that may give rise to a conflict of interest. The present slide contains some examples. The TCPS also addresses essentially the same information set out above in its separate chapter on clinical trials. A Rev in conducting its ethics review of proposed ongoing research is required to assess whether the researcher has a conflict of interest and, if so, to decide what action, if any, is needed to address the situation. For example, the Rev may require the researcher to disclose this conflict to prospective participants during the consent process to others, for example, research sponsors, research institutions, and relevant professional bodies. The Rev may prohibit some forms of payment or require the researcher to withdraw from the project or, in exceptional cases, refuse to approve the project where the conflict has not been avoided or cannot be properly managed. In closing, I note that Canada's regulatory framework for human biomedical research is mirrored by complexity. Nonetheless, researchers, Rev members, and research institutions need to adequately inform themselves of all the relevant regulatory instruments. A failure to adhere to these requirements can put the safety and well-being of research participants in jeopardy and can expose those involved in research to legal liability. Before I leave you, I want to quickly thank the DeHousey Health Law Institute for generously supporting the development of this module. Thank you very much for your attention.