Ethics application protocols for multicentre clinical studies in Canada: A paediatric rheumatology experience

Abstract

INTRODUCTION:

Individual institutions govern research ethics applications and each must administer and regulate their own protocols. Variations in ethics review procedures and expectations among centres impose impediments to efficiently conducting multicentre studies.

METHODS:

Observations relating to preparing multisite ethics documents for a study conducted by Canadian paediatric rheumatology investigators are described. Research ethics applications from the 12 participating centres were compared.

RESULTS:

Although the applications were similar in their content, they differed in their formatting. All applications shared a commitment to ensuring that the study conformed to exemplary ethical standards.

CONCLUSIONS:

There is wide variation in the multicentre clinical study ethics application process at the institutional level. Considering the common fundamental elements required by all ethics review boards, the present study conceptualized introducing a discipline-specific uniform ethics application process acceptable to all Canadian research ethics boards. This may be a more efficient strategy that could help lessen the burden of collaborative research.

Multidisciplinary, multicentre, collaborative research, which is emerging as an effective paradigm for biomedical research, is taxing the capacity of Canadian academic institutions to meet demands for human ethics reviews. As a result of experiences with collaborative multicentre research, members of the Canadian paediatric rheumatology research community have come to appreciate the daunting task of preparing the materials required by many different institutional ethics review boards for the same project. The objective of the present report was to review our experience with current ethics application processes in Canada in the context of the multicentre clinical study, Biologically-based Outcome Predictors in Juvenile Idiopathic Arthritis (the BBOP study). We have identified elements of the current ethics review system that could benefit from instituting a more coordinated, integrated approach to multi-centre paediatric biomedical research in Canada.

CURRENT SITUATION

In 2010, Canada’s national research funding agencies issued a second Tri-Council Policy Statement on Ethics in Human Research that clarified procedures regarding multijurisdictional research. Since the late 1990s, Canadian universities and research institutions have been responsible for the implementation of policy frameworks pertaining to ethics review. The most recent Tri-Council Policy Statement maintains that “the institution remains responsible for the ethical acceptability and ethical conduct of research undertaken within its jurisdiction” (1). Since the original statement in 1998 and its revision in 2010, each institution has individually developed rules, regulations and protocols governing their respective ethics application and review processes. The main reason institutionally based research ethics boards (REBs) were put in place was to protect the rights, safety and well-being of potential research participants, particularly in light of issues unique to geographically isolated populations.

A decentralized, institution-based, local ethics review approach functions well for small, single-institution studies but poses difficulties for larger studies, in part due to the requirements for different applications and consent forms for each institution. However, research studies often involve many investigators from multiple centres. Respective ethics review boards aim to ensure that research adheres to acceptable ethical standards and incorporates a clear and effective designation of responsibilities and accountability paradigms. Adjudicating complex ethics submissions can be a daunting task for reviewers, and a costly undertaking for both researchers and host institutions. In particular, for multicentre studies, multiple submissions to the various institutional ethics committees are required, resulting in added complexity, time delays and administrative inefficiencies. Uniformity of ethics protocols and procedures among institutions, while maintaining individual REBs, could lead to greater efficiency while still ensuring the research applies optimal ethical standards. Despite adherence to the same research project protocol, considerable time and effort is required to format ethics applications to comply with the different requirements of each individual centre’s REB. This process becomes a cumbersome and costly responsibility for complex multicentre studies.

Others have suggested that local review of multicentre protocols is not necessarily the best approach (2). For example, a national questionnaire-based study on the effect of birth weight on child development required submission of 1095 copies of the protocol, 1116 forms and additional supporting documentation to 145 different review boards in the United Kingdom (3). Responses of the review boards varied and 22% had not responded within three months (4). That study described the time and resources required to tailor the ethics application to a particular format as well as the problems that arose when dealing with a large number of ethics committees on a national scale. Based on their experience, common forms and a central review board were recommended.

The steering committee of the multicentre BBOP Study anticipated some variability in the research ethics application process and appointed one coordinating site to reformat all ethics applications and consent forms to comply with the formatting requirements of the 12 different REBs across Canada. Although this was an arduous task, it is our impression that the process was more efficient than having each centre prepare their own ethics application. The coordinating centre, while liaising with the principal investigator at the participating centre, then responded to each REB’s distinct requests for clarifications and modifications of the ethics and consent documents. In our experience, assisting sites across the country with preparing ethics submissions ensured a timely start to the study with involvement from all geographical areas with paediatric rheumatology representation. One lesson learned from the BBOP system was that it was important to maintain a close relationship between the coordinating centre and the peripheral sites, at the level of the principal investigator, research personnel and REB. Open communication about the protocol, application process and timeline was important to expedite ethics approval and sustain engagement of all participants. A number of subsequent Canadian multicentre studies in paediatric rheumatology have adopted a similar practice for preparing research ethics applications.

THE BBOP STUDY EXPERIENCE

Using the multicentre BBOP Study as an example, an observation was made that ethics application forms for the 12 centres involved were vastly different in formatting but essentially the same in general content. Table 1 provides a summary of the research ethics application content for the Canadian centres involved in the BBOP study. Ethics applications comprise two main sections: project registration, which provides the REB with information about the type of investigation, the names and credentials of investigators involved in the study, dates and duration, and financial support; and a description of the study including information about the study design, rationale, target populations, details about inclusion and exclusion criteria, and procedures for ensuring security and confidentiality of data. A small number of subsections within each section of the respective applications were not requested by all centres. However, most of the content was common to all applications and major differences were in the format as well as the number of copies required, which ranged from two to 18 paper copies. Only one centre at the time required electronic submission, with all other centres requiring paper-based submissions. In addition to differences in the REB application forms, differences in the basic elements of the consent forms were also noted. The majority of the 12 REBs involved in the BBOP study expected consent forms, assent forms and companion consent forms for genetic samples in formats unique to each institution. REB reviewers evaluated each form for the inclusion of the basic elements of informed consent specified in the federal regulations and assessed the degree to which the language used to describe the elements was complete and/or understandable. Only one REB allowed the combination of parental consent, child assent and genetic sampling consent into one seven-page document, thus necessitating only one set of signatures from the potential recruit. Two participating institutions required two separate forms; parental consent combined with genetic consent with an average length of 10 pages and the child assent with three additional pages, for a package total of 13 pages. Four sites requested an additional consent form for older children supplementary to the parental consent, assent for a younger child and genetics consent. The package of forms to obtain informed consent at these four sites ranged between 16 and 22 pages, with an average page total of 19. In summary, consent forms for this study varied between seven and 33 pages in total depending on the institution. This variability among centres begs the question: Which centre holds the ideal template for informed consent?

TABLE 1.

Description of common content. Overview of research ethics board application sections among the 12 participating Canadian centres in the Biologically-based Outcome Predictors of Juvenile Idiopathic Arthritis clinical study

Section title	Section description	Sites, n
Section A: Project registration
Project title		12
Applicant and centre information	Including coinvestigators and their institutions and participating centres	12
Type of investigation	Eg, clinical trial, drug study, chart review	12
Site of research	Eg, health region, sites, building, rooms	12
Dates and duration of study	Start- and end-dates	12
Funding sources and budget	Funding source (awarded versus pending)	12
Approvals	Eg, departments, Health Canada, safety	12
Other reseach ethics board submissions	Include approval dates	12
Lay abstract	Summary in plain language	3
Conflict of interest	Declaration of investigator remuneration	12
Coordinator/personnel information	Names, institutions, research units of those personnel involved	3
Authorizing signatures	Principal investigator and department head	12
Section B: Project description
Scope, objectives and hypothesis	Description of research question	12
Rationale and scholarly significance	Including references	12
Basic study design	Specifics of treatments or procedures	12
Sample size and calculations	Local and total participants	12
Target populations	Inclusions and exclusions	12
Procedures/interventions	Biological specimen storage, labelling methods, accessibility of samples, questionnaires and data collection forms used the study	12
Outcome variables	Description of end-point measurements	1
Recruitment and identification	Screening of participants, process of obtaining informed consent	12
Data analysis	Methods of analyses, secondary analysis	6
Data storage	How long data will be retained, procedures for securing written records	12
Risks/benefits	Potential harms, inconveniences and benefits	12
Privacy and confidentiality	Who has access to information	12
Compensation/costs	Describe compensation or reimbursement	12
Disclosure of information	Methods for disseminating research results to subjects	2
Supporting documentation required by all research ethics boards
Recruiting materials and participant information sheets
Consent forms, assent forms and companion consent forms for biological samples
Questionnaires
Itemized budget
Proof of award of funds
Schematic of study timeline
Curriculum vitae of the principal applicant (site specific: 4/12 sites)

OTHER EXPERIENCES

In the context of a multicentre study, duplication of effort and inefficiency associated with numerous local reviews of the same study are concerns that have also been noted by others (5,6). The consensus is that not only are the majority of institutions requiring specific forms for the ethics application, but they also vary in both their response time and ultimate decisions. Edwards et al (2) performed a systematic review of literature, published over a 20-year period, that compared ethical judgments made by different review boards when reviewing one or more protocols. Included was an analysis of 17 studies that presented data on how different boards reviewed a single protocol. Of the 17, five studies reported that some review boards approved while others rejected the same protocol. All 17 studies reported differences in the protocol revisions requested as well as the questions and issues that arose surrounding the revisions. For example, Stair et al (7) documented variability across 44 institutional review boards in 17 states in their initial response to a single clinical trial protocol. Ultimately, all sites gave approval but not without considerable time and effort by both investigators and institutional review board members. Eight studies reported differences in the approach to consent, similar to our experience with the BBOP study (7). In particular, with juvenile subjects, research ethics committees focused on the children’s status as vulnerable and expressed concerns about consenting procedures as well as emphasizing the need for children to be protected in research (8). The documented variability in these studies, as well as our experience with the BBOP study, represents an important burden to investigator-initiated multicentre studies, particularly those administered on limited budgets. In a small centre that only recruits relatively few subjects, the amount of time required for preparation of an REB submission would be comparable with a large centre but disproportionately greater relative to the number of subjects enrolled.

POSSIBILITIES FOR IMPROVEMENT

Seeking approval for a study that includes multiple centres that draw subjects from a large geographical area is time-consuming and expensive for researchers and ethics committees. These issues, together with concerns that, despite guidelines, local committees differ widely in both their application requirements and responses, suggest that there is a need for improvement among national ethics procedures that would facilitate multicentre paediatric clinical research. We conceptualize that there could be a common ethics application form used when applying to multiple Canadian academic institutional REBs. Such an approach would eliminate the need to prepare different submissions to comply with each institution’s formatting requirements. A standard application form available electronically would reduce the time and cost for both local committees and researchers. In this model, each individual REB would review the application and maintain legal and ethical responsibility; therefore, the expectation is that study participants would be optimally protected. Harmonization of the application process would simply be more efficient and cost-effective. If harmonization did lead to improvements in the efficiency and clarity of consenting to and conducting a study, the result would be of direct benefit to subjects. In addition, if administrative costs for REB submission and approval could be reduced, more funds would be available for research purposes and less required for administration.

It is acknowledged that even a simple change to the research ethics application could carry feasibility issues because there would be ethical, legal and administrative concerns to overcome. As a first step, a national task force consisting of consulting members from each academic institution would be necessary. Dialogue in consultation with members of the various REBs, bioethicists, researchers and clinical research coordinators would have to result in agreement about the information to include, the presentation format, number of copies and accessibility of the forms. In addition, there would be costs associated with initial programming as well as programming changes of common electronic forms. Institutions interested in reducing these expenses may be persuaded to work together to adopt a framework from existing electronic REB systems. Although these types of changes may seem unachievable, others have effectively implemented harmonized ethics applications and review (9).

DIFFERENT MODELS OF ETHICS REVIEW FOR MULTICENTRE STUDIES

Common ethics application forms have been and are being used successfully; however, this concept generally exists where a centralized review system is in place. There are a number of examples in which research ethics review is conducted by a single, central review board and principal investigators have one contact point and one application. Province-wide initiatives include the Ontario Cancer Research Ethics Board, where local institutions can elect to use the central board for either an expedited review process or a complete delegation of ethics review responsibility for multicentre oncology research (9). The Ontario Cancer Research Ethics Board has successfully lessened the submission workload, as well as expedited and coordinated the start-up of many cancer clinical trials in Ontario. Newfoundland and Labrador has also established a central provincial Health Research Ethics Board to review all health-related research, including clinical trials and genetic studies (10). Earlier this year, six REBs in Alberta signed a Research Ethics Reciprocity Agreement with the short-term goals of implementing a common application form, common consent guidelines and a process for dealing with multisite health research ethics review (11). Quebec has also experienced centralized review for three years (12). From an administrative perspective, these systems function to decrease redundancy province-wide and provide improved protection for research participants. While these efforts to harmonize within provincial jurisdictions are a step in the right direction, we believe that national uniformity across disciplines may be even more desirable. This is particularly relevant to trials that study childhood rheumatic diseases for which national, interprovincial collaboration is required. Indeed, other countries have implemented central ethics committees with varying degrees of success, including Portugal (13), the United Kingdom (14) and the European Union (15). Australia also recently announced that it is committed to harmonization of its multicentre ethical review process (16). In addition, the United States Department of Health and Human Services recently announced a proposal that includes using a single institutional review board for all domestic sites of multisite studies as well as updating forms and processes used for informed consent (17).

There are advantages to having a centralized ethics review board, including lower administrative costs per review, less demand on limited human resources and greater consistency of reviews. Furthermore, centralized review boards facilitate access to expert panels comprised of representatives from a variety of disciplines. It is possible that a national review board responsible for vetting the ethical standards of research protocols coupled with local autonomy for overseeing adherence to ethical conduct could effectively enhance efficiencies while ensuring research subjects are protected (18–20). However, there are also drawbacks to a unified review system. A centralized REB may not be able to adequately respond to regional, cultural and geographical differences. It is for this reason that others have suggested that multiple REB reviews, despite the inefficiencies, may promote human research protections (21). In our experience with the BBOP study, the most inefficient part of the ethics process was the preparation of the documentation. This led us to consider the concept of standardizing the application, not necessarily centralizing the REB.

Although progress has been made since the original ethics review system was developed in the early 1990s, improvements to the process are necessary to adapt to the changing nature of how research is now typically conducted. There has been a shift from federally funded studies performed at a single academic centre to larger multicentre, multidisciplinary studies. The Canadian Network for Public Health Intelligence has recognized this and developed a collaboration centre for multicentre research projects, posting the decisions of REBs on registered projects so that other REBs can review previously made decisions before deciding locally (22). This initiative coupled with common ethics application processes acceptable to all Canadian biomedical REBs would create a national standard of research ethics for multicentre studies in accordance with current guidelines (1). If collaborative research is to be fostered and encouraged, it is to both the patient’s and investigator’s benefit to simplify the process, thereby helping to minimize the initial burden on the investigator while still ensuring adherence to acceptable ethical standards.

CONCLUSION

A more effective and efficient approach to multicentre paediatric research is required because the current disparate system places too large a burden on both the investigators involved in multicentre studies and the local REBs. The consideration of a common ethics application form and consenting process might be an important first step to harmonization of the ethics review process for multi-centre paediatric studies in Canada.