Research in Multiple Settings (PDF, 192 KB)
Prepared by the
ProGroup recognizes the valuable input and thoughtful contributions of the late Dr. Mike Enzle (a former ProGroup member) to this work.
The content and views expressed in this document are those of members of this committee, and do not necessarily reflect those of the Interagency Advisory Panel or Secretariat on Research Ethics.
The Panel and Secretariat welcome your comments: firstname.lastname@example.org
The need to clarify and develop a common understanding of what falls under a “Multicentred Ethics Review”, how to enable the existing traditional conventional Canadian model of ethics review by single Research Ethics Boards (REBs) of research requiring multiple REB involvement, and to further explore other alternatives for ethics review of multicentred research have been identified to require clarity and further development in the current Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS). To remedy this situation, ProGroup, a working committee of the Interagency Advisory Panel on Research Ethics (PRE), presents in this paper, discussions and proposals to better reflect the ethics review process of multicentred ethics review. The paper introduces the new concept of “research that may require multiple REB involvement” to replace the current “review of multicentred research” to better reflect the spectrum of REB involvement based on a proportionate approach to ethics review. The paper presents and makes textual recommendations to the TCPS on a description of what falls under research requiring multiple REB involvement. It introduces some alternative models of review that exist nationally and internationally to supplement the current model of ethics review by single REBs. These models or a mix of those are presented as options for flexibility in application for the range of disciplines covered by the TCPS. Their success is context driven and determined by several factors outlined in the paper.
The paper does not propose specific textual changes to the TCPS, but provides a list of some factors that potentially contribute to an effective ethics review process requiring multiple REB involvement. These include elements such as a decision-making framework for the selection of an appropriate multiple REB model, multiple REB communication and transparency, essential education in the ethics review of research requiring multiple REB involvement, securing adequate resources to support the ethics review process that involves multiple REBs, and addressing operational issues. In the paper, ProGroup identifies issues of liability and risk management that have emerged from ProGroup’s work. These issues are listed and proposed as a starting point for further development by experts in liability and risk management.
ProGroup anticipates that the community input on this paper will lead to refinements to the proposed textual recommendations of review of research requiring multiple REBs involvement for more clarity, detail and prominence in the TCPS.
Almost 20 years ago, in 1987, the ethics guidelines for research involving humans of the former Medical Research Council of Canada referred to multicentre trials1. When the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS)2 was adopted a decade later, it also briefly addressed ethics review involving multicentred research, with intended application across the disciplines of Social Sciences and Humanities, Natural Sciences and Engineering and Health Sciences, the range of disciplines supported by the three Agencies3.
Subsequent developments have since confirmed challenges presented by the issue of the ethics review of research requiring multiple REB involvement (previously multicentred ethics review), particularly in the face of increasing collaborative research projects and networks involving researchers at more than one institution. Initiatives like the Tri-Agency Networks of Centres of Excellence4, and other Agency specific collaborative research initiatives and programs have synergized opportunities for collaboration to advance new research knowledge, but such collaboration has presented challenges. When a researcher, team or network proposes a project that requires conducting research involving humans at multiple institutions or sites across a provincial, national or international borders, for instance, the project encounters the prevailing model of ethics review in North America: prospective ethics review by interdisciplinary institutional research ethics boards (REBs) at the local level.
Local ethics review of the research project at every institution injects assembled expertise, analysis, and values into the project5. Multiple, independent reviews also risk yielding inconsistent ethics review processes, redundancy, and delays or inefficiency for time-sensitive research6,>7,8. The costs of multiple reviews, some argue, are unlikely to confer added benefits 9, 10.
The dynamic has prompted questioning of the existing model, a search for alternatives, and further study and clarification in the TCPS of ethics review of multicentred or multisite11 research.
Since its creation in 2001 by the Agencies, the Interagency Advisory Panel on Research Ethics (PRE) has had a mandate to steward the evolution of the TCPS. In March 2003, in response to the recognized need to address procedural and definitional issues in the TCPS, PRE created the Sub-group on Procedural Issues for the TCPS (ProGroup)12. ProGroup was mandated to provide advice about priorities, methods and mechanisms for identifying gaps and procedural and definitional issues within the TCPS, and to coordinate a response to those issues.
Consistent with PRE’s basic processes and principles, ProGroup’s work is based on transparency, community engagement and consultations. Based on public consultations and feedback from the research ethics community in 2003 to identify13 and prioritize14 procedural and related definitional issues in the TCPS, ProGroup has identified a need to study several issues related to the TCPS. One of these includes clarifying and further developing Multi-centred Ethics Review in the TCPS. Discussions and consultations revealed the need to:
The Interagency Advisory Panel on Research Ethics’ “Response to the Draft Report of the Experts Committee for Human Research Participant Protection in Canada” (22 November, 2007) also identified multicentred ethics review as a critical area in need of attention in the TCPS. ProGroup refers readers to this document15 for further deliberation within the Canadian context.
This paper focuses on proposals and makes recommendations that address multicentred ethics review issues not yet considered in the TCPS, but identified as matters of concern during the consultations. It does not purport to identify or resolve all outstanding issues related to multiple REB involvement/multicentred research. While ProGroup recognizes the need to address issues and controversies in the ethics review of research at multinational and global levels, at this stage, the committee is only addressing the conduct of research requiring multiple REB involvement at the national level. Addressing it at the national level first will ultimately set the base for others, as they might be considered at a second stage. The paper is developed within current context recognizing the need to observe, acknowledge and respect the dynamic nature of research ethics review in this area.
ProGroup encourages comments and reactions to this report from research ethics administrators, research ethics board members, researchers, research subjects16, policy makers, and interested parties. Such input will help inform the drafting of textual recommendations related to the multicentred ethics review in the TCPS for consideration by PRE.
This discussion paper represents ProGroup’s work on the area of the ethics review that requires multiple REB involvement including multicentred research in the TCPS. It was produced, in part, with the assistance of Virtual Scholars(VS)17 who conducted research and study in the area of procedures for multi-centre human research ethics review in support of ProGroup’s work on this area in October, 2005. It was supplemented by an additional literature review by the Secretariat on Research Ethics reflecting the most recent developments and contribution to the area. It was further complemented by the practical experience and expertise of ProGroup members as well as members of the sounding board dedicated to this area. Sounding board members18 provided input on the authors’ initial thinking on the area, as well as through feedback on drafts electronically and in face-to-face workshops held in May, 2007 and February, 2008.
The existing TCPS offers some, but limited, guidance on the topic of multicentred ethics review, and has, therefore, been identified in public consultations to require clarification and potential revision. At least three provisions of the TCPS address ethics review of multicentred research. Together, they
The institution in which research involving human subjects is carried out shall mandate the REB to approve, reject, propose modifications to, or terminate any proposed or ongoing research involving human subjects that is conducted within, or by members of, the institution, using the considerations set forth in this Policy as the minimum standard.
Each institution is accountable for the research carried out in its own jurisdiction or under its auspices. An institution can authorize its REB(s) to accept the review of other REBs constituted under the Tri-Council Policy Statement if it so wishes. This might involve specific agreements between institutions for sharing the work.
Principles of institutional accountability require each local REB to be responsible for the ethical acceptability of research undertaken within its institution. However, in multicentred research, when several REBs consider the same proposal from the perspectives of their respective institutions, they may reach different conclusions on one or more aspects of the proposed research. To facilitate coordination of ethics review, when submitting a proposal for multicentred research, the researcher may wish to distinguish between core elements of the research—which cannot be altered without invalidating the pooling of data from the participating institutions—and those elements that can be altered to comply with local requirements without invalidating the research project. REBs may also wish to coordinate their review of multicentred projects, and to communicate any concerns that they may have with other REBs reviewing the same project. The needed communication would be facilitated if the researcher provides information on the institutional REBs that will consider the project.
Similar to the TCPS, the Good Clinical Practice19 (GCP) to which Canadian institutions adhere for the conduct of clinical trials provides some guidance for the review of multicentre trials under a coordinated effort20. The GCP defines a multicentre trial as “A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.”
Issues with the ethics review of multicentred research, the variation of requirements, and lack of uniformity amongst local REBs is not confined to the TCPS, or limited to the Canadian context. Such issues have arisen at the provincial level within Canada. For example, in 2007, the Quebec Ministry of Health and Social Services has developed a mechanism21 for the ethical review and monitoring of multicentred research. Other examples of initiatives in development include Alberta and Newfoundland, and the Canadian General Standards Board on behalf of Health Canada. Some have conducted evaluations to explore the challenges of obtaining research ethics board approval of multisite studies22. Others have suggested steps to be taken to improve inter-institutional coordination and cooperation in ethics review and other aspects of human subject protection, and provide an overview of some existing models in Canada, the UK and the US.23
Internationally, other countries24, such as the US25, and the UK26 face similar challenges in the review of multicentred research and their success has varied and developed with experience. While similar concerns seem to transcend from medical to health to social sciences and humanities and to natural sciences and engineering research conducted in multisites or multicentres, the issues seem to have received more attention in the clinical research contexts as evidenced by the available literature in the area. What has been helpful in shedding some light on the applicability of such issues to other disciplines and the potential unique challenges posed to research in other disciplines are the results of the interviews conducted by the Virtual Scholars in 2005. Close to 20 experts representing a variety of disciplines and roles in research and ethics review were interviewed. While the results are based on a limited number of interviews, they bring value considering the lack of literature and policy in these areas. They also confirm the clear need for further direction and further policy development taking the spectrum of research and research disciplines into account. Feedback from interviews within this limited pool of respondents revealed that researchers and institutions are challenged in practice with coordination efforts of ethics review of multicentre studies in the area of social sciences and humanities.
In looking closely at issues of multicentred ethics review, there is a variety of points of view. On one hand, and as outlined by some in the literature27, some value the benefits of ethics reviews done at multiple sites. The number of REB members who participate in the review process and the diversity and variability of their experience and expertise bring a higher level of assurance in the ethics review process; such that the dissenting opinion of one of many REBs reviewing the same research may serve to identify an omission relevant to human subject protections that other reviewing REBs may not have seen e.g. risk of harm dependent on particular characteristics of local populations. Furthermore, REBs apply other local, provincial and territorial policies and guidelines that may bring new requirements or elements for consideration, and thus may contribute to a strengthened ethics review of research. Above all, multiple reviews are likely to promote and increase trust in the ethics review process and human research protection in general.
On the other hand, several concerns have been raised by the current system of multicentred ethics review process, most of which center on inefficiency and inconsistency as reported by the Virtual Scholars as well as in the literature 28, 29. Multiple reviews of the same study may result in the following:
There seems to be several possible reasons for the variability in ethics review process, decision making and the outcomes of reviews as outlined by some30, and confirmed by the Virtual Scholars’ interviews:
ProGroup recognizes the need to develop a common understanding within the research ethics community of what constitutes multicentred ethics review. In order to facilitate such a development, ProGroup makes the following proposals based on an analysis of the current situation, and building on the input of experts of the sounding board at face-to-face meetings:
These proposals are to be complemented by strengthening the “proportionate approach” to ethics assessment for research requiring multiple REB involvement. Using the new terminology will also allow for a shift from the current “multicentred” that has been perceived to give a biomedical connotation. Also, the following proposes making necessary references to other relevant procedures in the TCPS such as the Continuing ethics review that should be agreed to at the outset following TCPS Article 1.13.
Research that May Require Multiple REBs Involvement:
Research involving humans that may require the involvement of multiple REBs includes, but is not limited to, the following:
Multiple REB involvement can range from conducting multiple reviews of the same project or of its elements, to accepting the review of other REBs constituted under the TCPS (as per Article 1.2). The decision on the level of ethics review of research that may require multiple REB involvement should be proportionate to the risk involved in the research. Continuing ethics review for such research should follow the same process developed for the initial review provided the risks have not changed, and following Article 1.13 of the TCPS.33
Some models exist both nationally and internationally, with variability in their success in addressing multicentred issues. ProGroup identified the following models to complement the Canadian conventional ethics review by institutional REBs. These models provide options and flexibility in their application for the range of disciplines covered by the TCPS. However, the intent of this document is not to prescribe a specific model for certain types of disciplines. Several factors need to be considered in making a decision on the selection of an appropriate multiple REB model as will be stated in section4 of this document.
Models for the Ethics Review of Research that May Require Multiple REB Involvement:
The success of ethics review models involves consideration to context. The context is to be determined by the discipline being reviewed, relationships between REBs, and between their institutions, the availability of appropriate experience and expertise within or available to the reviewing REB, the scope of the project under review and the study population, the potential for conflict of interest and undue influence, and the level of risk associated with the research under review. Federal, provincial and territorial policies and legislations, and institutional requirements also need to be taken into consideration. The use of one or a mix of the following models should be informed by the basic requirement of the TCPS as per Article 1.2 of the TCPS that research ethics remains the responsibility of the institution.
The following models37 are intended to provide options and flexibility in their application for the range of disciplines covered by the TCPS. At the onset, roles and responsibilities of all involved in the process need to be clarified and agreed to. Whichever model is adopted, it needs to follow the guiding ethical principles of the TCPS (page i.5) with the underlying goal of research participant/subject respect, protection and safety.
In order to plan and build the appropriate model of ethics review of research involving multiple REBs, ethics needs to be an integral part of the research, and not an afterthought. The development of a model is a collective/collaborative responsibility that involves the institution, researchers, and REBs. It ought to be informed by the subject-centered focus of the ethics review process, and basic requirement of the TCPS that research ethics remains the responsibility of the institution as per Article 1.2 of the TCPS. Special attention needs to be given to the particular characteristics of local populations. Therefore, a pure Central REB model does not respect the principles of the TCPS. Only a hybrid central model taking into consideration the needs of local populations would respect the subject-centered focus of the TCPS, and the responsibility of the local institution. Such a hybrid central REB model would inform and facilitate the decision-making process for the local institutional REB which should not abdicate its roles and responsibilities. In general, the above should be taken within the evolutionary nature of the TCPS that will require further reflection and deliberation with time.
Sensitivity to context is a key issue in the process of ethics review. There is a need for flexibility and empowerment for REBs to respond to different situations based on context, for example, local, provincial, and national requirements. A balanced perspective suggests that a unified response by all involved REBs is not expected, but a consistent framework of ethics review ought to be applied with clear roles and responsibilities, and with a framework for decision-making processes.
From this point on in this document, the objective is to provide some background material that informed and guided ProGroup’s presentation and recommendations for the proposed revisions to the TCPS (Section 3 of this document). The following sections will hopefully provide explanations and suggestions for further development in this area.
As already stated, the success of the ethics review model (that may be one or a mix of the above models) selected involves consideration to context. The context may be determined by, but is not limited to:
Defining and understanding the discipline and field of research will facilitate identifying the appropriate REBs and the appropriate model to review the proposed research. Such an understanding of the discipline and field of research should be first informed by input from the researcher. Normally, the researcher would propose a model, and the REB would consider the proposed model and subsequently make the decision on the selection.
For matching the disciplines, fields of research with the appropriate REBs, specialized research ethics boards such as pediatric, social sciences, biomedical, population health, education...etc. need to be recognized and understood by all involved in the research and research ethics process. For example, some REBs are specialized in areas such as oncology, population health, social sciences and education, amongst others, and these would be logical choices of REBs to select in addressing those disciplines or fields of research.
There are a variety of formal and informal REB Chair, members, and administrative relationships already established in Canada. These established links may be useful in facilitating and informing the selection of a model by REBs.
As stated in the commentary to Article 1.2 of the TCPS: “Each institution is accountable for the research carried out in its own jurisdiction or under its auspices.” Institutions delegate the authority to the REB through their normal process of governance. Delegation of authority takes various forms and involves a variety of relationships within institutions. The nature and dynamic of these relationships between REBs and their institutions is likely to influence the adoption of the models selected by the REBs.
It is worthwhile noting that this is a key issue in this discussion paper – what is the role and authority of the REB – the paper alludes to the fact that the REB has the power to accept alternate modalities, when, in fact the institutional legal liability, and risk assessors will more likely make the determination.
REBs may not always have the expertise or experience to adequately assess the acceptability of other REBs or inter-institutional agreements. These decisions are not lightly made, and can take considerable time to implement depending upon the policies at each institution. In some cases, it may just be easier and faster to do the multiple reviews than to orchestrate multi-institutional agreements and arrangements especially if the project meets the institution’s guidelines for delegated review.
The relationship between an investigator and his/her REB is essential in informing the selection of the appropriate model, and serves as a two-way education process. Therefore, early communication is necessary between investigators and REBs about proposed research and the scope of the project(s) that will require multiple REB involvement. For example, as a practical application, it may be helpful to suggest a mutually agreed upon multiple REB review process-map that a primary investigator/lead researcher and home institution could then follow and update as necessary. This does not only inform the models to be selected, but may also guide the selection of the number and nature of REBs to be involved in addition to the local REB, potential institutional or REB constraints, and the development of links with other institutional REBs and researchers. The final decision regarding the appropriate model to be implemented is the responsibility of the principal REB.
To enable and empower REBs to take advantage of relationships such as reciprocal REB arrangements, identification of education, skills and experience available within a particular REB will be necessary for the selection of the model. Sharing of information such as terms of reference and documentation is essential to facilitate such arrangements. REBs may request the input of external expertise not available from its regular members. Should this occur regularly, the membership of the REB should be modified to add this expertise in accordance to commentary to Article 1.3 of the TCPS.
In selecting the appropriate model for ethics review, the REB should pay particular attention to the possible conflict of interest e.g. the interrelations between researchers that may influence the protection of subjects. Some of the models might help in reducing perceived, potential, or real situations of conflict of interest or undue influence, and some may increase it.
Generally, the level of risk associated with the ethics review of research in multiple settings and/or involving multiple REBs is no different from the level of risk of the same research if requiring a single REB review. However, in selecting the appropriate model and determining the level of involvement of REBs in the review process, it is essential that REBs take a proportionate approach. This would depend on the level of risk involved in the research. Special attention should be given to the study population and the level of involvement of members of their institution in the research. The level of involvement of an REB might range from conducting ethics review to noting that a review has taken place in another jurisdiction.
As previously outlined in the document, the TCPS, through the May 2000 amendment, states that “Each institution is accountable for the research carried out in its own jurisdiction or under its auspices. An institution can authorize its REB(s) to accept the review of other REBs constituted under the Tri-Council Policy Statement if it so wishes. This might involve specific agreements between institutions for sharing the work.” Institutions must respect the authority delegated to the REB. However, institutions may refuse the REB’s selection of certain models for research requiring multiple REB involvement, even though the REB has found it acceptable.
Factors contributing to an effective and successful process of ethics review of research involving multiple REBs may include, but are not limited to, trust between local committees; supportive policy environment through buy-in of participating institutions; and connection and ongoing communication between central and local REBs. Transparency would facilitate the ethics review process involving multiple REBs by allowing access to, and appropriately engaging the local context. To facilitate this process, REBs may consider, and some already do, public sharing (e.g. by posting on the internet) of their institutional policies, procedures, and templates of consent documentation and application forms used to guide the operations of their REBs.
Appropriate education and comprehension of the ethical framework of the TCPS is at the heart of this process. It is essential to raise awareness of the viable models, available options as well as flexibility that exists to effectively operationalize multiple REB review in Canada. To do so, REBs may consider making public the REB models that they have adopted, and criteria for the applicability of the models to their research.
The nature of the ethics review of research involving multiple REBs requires the dedication of time, effort and financial and human resources. The level of resources will depend on the selected ethics review model and whether these are ad-hoc or ongoing needs. The availability of resources will facilitate an effective conduct of REB review, will likely enable REBs and encourage them to be responsive, potentially yielding shorter times for completing the ethics review process. It is appropriate to operationalize the additional resource requirements for this type of ethics review. Options to secure such resources are proposed in section 6 of this document.
The following REB operational issues deserve appropriate attention and consideration for the success of the ethics review of research requiring multiple REB involvement.
This may include the development of a basic set of requirements and documentation on which institutions can build, e.g. templates of information consent documentation, applications forms, research ethics review tools to encourage transparency, reproducibility, generalizability, and potentially contributing to consistency and harmonization of activities between REBs.
Institutions should enable their REBs to complete ethics reviews within shorter time frames. When selecting a model that have multiple REB reviews, the more REBs are involved, the more attention should be given to responding to the review results within limited timelines. In such case, serious consideration should be given to the proportionate approach to ethics review, to the timing of conducting parallel reviews, and to facilitating the process to integrate them.
As with the commentary to Article 1.5 in the TCPS; “REBs should normally avoid duplicating previous professional peer-review assessments unless there is a good and defined reason to do so.” This is particularly crucial in ethics review involving multiple REBs.
It is essential to keep an official record of all necessary documentation related to the agreed upon multiple REB review process. Records may include minutes of REB meetings (as per Article 1.8 of the TCPS), pertinent agreements, or other documents on which an REB makes a decision. REBs may have different requirements for operational issues such as record keeping.
The continuing ethics review process and the process of reporting amendments and adverse events ought to be negotiated and agreed upon at the time of selecting the multiple REB review model. It may follow the same process as the initial review, but may include requests for additional information as required, especially if the risks of the research have changed.
As with the above, the process of reconsideration and appeals for the ethics review process that involves multiple REBs needs to be negotiated and agreed upon at the outset.
There should be clarity and agreement on identifying a contact for research subjects in case of complaints about the research and how they would be resolved. It is also necessary that the contact keeps all involved REBs abreast of such complaints and how they have been addressed.
This section is intended to provide some identified issues of liability and risk management that have emerged from ProGroup’s work on the ethics review of research requiring multiple REB involvement. Time limitations have not allowed ProGroup to pursue this very important work. ProGroup supports the conduct of an appropriate consultative process to effectively discuss the issues of legal liability and risk management to inform the development of policy recommendations.
Issues of institutional accountability, insurance and liability have been one of the main reported challenges to the development of multicentred agreements and delegation of review to a central or shared REB models as reported by the Virtual Scholars. As presented in May 2007, at ProGroup’s request and support, at the CAREB annual general meeting on the topic of institutional liability concerns, “Risk will always be present for Institutions engaged in research. The challenge is to find the right balance between acceptable risks and the benefits of the research.” and we “must acknowledge that different Institutions operate in different environments and have different appetites for risk.” 38
As previously indicated in this document, one of the May 2000 updates to the TCPS, at the end of Section 1.B1 (page 1.3), extends the authority of an REB to accept the ethics review of research done by other duly constituted REBs as per the TCPS guidelines. This might involve specific agreements between institutions for sharing the work. However, each institution remains accountable for the research carried out in its own jurisdiction or under its auspices. An interpretation by the Agencies of this amendment, and later confirmed by PRE in one of its interpretations39, outlined some of the basic requirements that may apply for this provision of sharing a review requiring multiple REB involvement amongst institutions:
The following are examples of basic elements that could be considered for inclusion in agreements. They are by no means proposed as fully representative.40
ProGroup identified the following issues and concerns that may need to be addressed by experts in the field of legal liability and risk management regarding ethics review of research requiring multiple REB involvement.
Research involving humans that requires multiple REB involvement also requires buy-in, trust, and adequate resources for all those involved. It is, therefore, proposed that Tri-council policies and funding for research ethics in general, and more specifically for ethics review of multiple REB involvement, be developed in the following areas:
Variations in viewpoints persist in the ethics review of research requiring multiple REB involvement in the TCPS. Some individuals, including researchers, some REB members and administrators, believe in taking advantage of mechanisms that streamline REB review procedures and decrease redundancy, time and cost of reviewing the same application at multiple sites. Others have expressed concerns about the sharing or delegation of authority partly due to issues of liability and accountability, and partly due to the potential for diminishing the institutional ability to ensure the ethical acceptability of research conducted within its jurisdiction in accordance with its own standards. The latter may be partly attributed to the requirement in the TCPS of 1998 that each institution is fully responsible for research ethics review of research conducted under its auspices. In 2008, ProGroup respectfully submits this paper for deliberation and comments to facilitate appropriate revisions to the previous multicentred ethics review section of the TCPS.