Canadian research ethics boards and multisite research: experiences from two minimal-risk studies.
Institutional review boards (Research ethics) (Powers and duties)
Medical research (Innovations)
Medicine, Experimental (Innovations)
|Publication:||Name: IRB: Ethics & Human Research Publisher: Hastings Center Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Hastings Center ISSN: 0193-7758|
|Issue:||Date: May-June, 2010 Source Volume: 32 Source Issue: 3|
|Topic:||Event Code: 350 Product standards, safety, & recalls|
|Product:||Product Code: 8000200 Medical Research; 9105220 Health Research Programs; 8000240 Epilepsy & Muscle Disease R&D NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences; 92312 Administration of Public Health Programs|
|Geographic:||Geographic Scope: Canada Geographic Code: 1CANA Canada|
Numerous studies have identified the challenges researchers face
when attempting to obtain ethics approval for multisite studies. For
instance, Greene and Geiger have identified delays in achieving ethics
approval across sites, excessive associated costs and resource
expenditures for achieving review at multiple sites, and variability in
requested changes by local research ethics boards (REBs) to study
materials, including consent forms. (1) Some researchers have stressed
the impracticality of submitting study materials to multiple REBs, while
others have pointed out that variability across REBs actually results in
less protection for research participants. (2)
In Canada, the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS) lays out the ethical requirements for publicly-funded human subjects research. The TCPS mandates that "All research involving living human subjects requires review and approval by an REB." (3) The implication of this policy for multisite studies created the requirement (also found in other research ethics guidelines) for local REB review at each study site. Accordingly, the TCPS states that each local REB is held "responsible for the ethical acceptability of research undertaken within its institution." (4) The recently revised TCPS (draft second edition) adds an entire chapter on the review of multisite research that responds to concerns in gaining ethics approval for multisite ("multijurisdictional") research. (5) It is unclear, however, if the proposed changes rely on the experience of Canadian researchers or on evidence about existing challenges or solutions that work. Indeed, there is scant evidence about how researchers have dealt with the TCPS's standards for obtaining REB review for multisite studies. In order to inform the debate about multisite REB review, we report our own experiences dealing with REB approval of two multisite, minimal-risk studies.
While conducting two multisite, minimal-risk studies funded by the Canadian Institutes of Health Research (CIHR), we realized retrospectively the interest of reporting our experiences and identifying some of the key features of the process of obtaining REB approvals from multiple sites. The first study, study A, examined the REB review process for neuroimaging research in leading Canadian research centers. The second study, study B, examined current and emerging issues related to the use of neurostimulation techniques such as deep brain stimulation (DBS) in leading Canadian neurosurgical units. Both studies involved minimal-risk methods with nonvulnerable populations and were conducted at Canadian academic research institutions and affiliated hospitals. Eric Racine was the principal investigator (PI) for both studies; Constance Deslauriers was the coordinator for study A, while Emily Bell was the coordinator for study B (see Table 1 for an overview of both studies). The value gained by addressing these research questions from a multisite perspective was paramount. We sought to identify national perspectives and required national representation, both to achieve a reasonable sample size and in order to be able to inform national policy-makers on these matters.
For each REB application, we identified the documents submitted for ethics review, the type of review granted (exempt, expedited, or full), and the number of days between submission date and receipt of approval. We identified the number of days for REB approval from the time we submitted study materials to the local PI and from the time the PI submitted the materials to the REB. We also identified the changes requested by each REB regarding the informed consent form; the research protocol and ethics approval application form; advertisement material; and study tools (e.g., interview grids and questionnaires).
Between May 7, 2007, and March 13, 2009, we submitted applications to 15 sites for study A and to seven sites for study B. An additional site for study A was dropped because the local PI agreed to submit the protocol but never did. Nearly all of the REBs used an expedited review process (n = 18/22; 82%). Three of the REBs used the full review process (14%); two of those REBs did so because they did not have an expedited review process in place. One REB (A5) determined that the application submitted was exempt from the need for REB review even though the study involved human subjects and we submitted some material for initial review (see Table 2).
Table 2 shows that the time from when we submitted the application to the local PI to approval by the PI's REB ranged from four to 546 days. Some sites did not require a local PI or were sites where Racine held local PI status (this information is listed as not applicable in Table 2). We also attempted to calculate how much time went by between when the local PI submitted to the REB and receipt of final REB approval. We were unable to obtain this information for six submissions despite repeated attempts to some REBs (three e-mails and two phone calls). For the 15 others, the number of days ranged from three to 489.
All submissions included copies of study tools, and most included the full protocol (n = 21/22), the consent form (n = 20/22), recruitment documents (n = 20/22), and a completed ethics approval application form (n = 17/22). Only one electronic submission was conducted through an online system for both study A and study B. Few REBs received and approved the study with the exact same combination of documents (for study A, REBs A2 and A4, and A11 and A13; for study B, REBs B3 and B7). Some REBs had singular requirements. For example, A14 and B4 required a checklist to be submitted; A3, A12, A14, and B4 required letters of support (from the local PI's department and sometimes also from Racine's institution); A15 and B5 required that the PI and graduate students involved in the study complete a TCPS certification; and B5 and B6 required additional applications for institutional approval because of the involvement of university hospitals. We observed a few discrepancies in the requirements of submissions to common sites (e.g., A2/B2; A10/B6; A14/B4; A15/ B5), but these could be due to changes in REB requirements, given the time span between our submissions.
Table 3 provides details about IRB queries and requests for changes regarding the consent form; the ethics approval application/study protocol; the recruitment advertisements; and the study tools. Most of the queries dealt with consent forms (n = 62/155; 40%) and the ethics approval application form/study protocol (n = 59/155; 38%), and most were requests for further information and clarification or for additional documents (n = 109/155; 70%). Less than a third of the REB responses were requests for us to make changes in the documents we submitted. Of the requested changes, the vast majority had a very limited impact on the nature of the research projects (e.g., change in format of study tools, change in format of consent form). Perhaps the most significant change from a research perspective was two REBs' refusal to allow the use of online survey software for study A. This was due to privacy concerns because the server was located in the United States and therefore subject to the USA Patriot Act of 2001, a law that allowed federal monitoring of some telephone and e-mail communications, as well as medical, financial, and other records, without the knowledge of those involved.
In many cases, the submission of our multisite projects involved a search for a local PI to submit the protocol for local approval (n = 18/20 sites; excluding the PI's institution but including institutions of co-PIs listed on the CIHR grant applications). In general, institutions varied broadly in their description of the qualifications for the local PI (i.e., giving no description at all of the role of the "local principal investigator" to precise specifications regarding who would be considered a local PI, such as a staff member or academic faculty member). Although we did not collect data on the search for the recruitment of local PIs, this process was time-consuming and complicated, usually requiring that we ask several colleagues to submit the project on our behalf and act as intermediaries during the REB review process (passing along requests for revisions and final hard-copy approval of the studies).
Our experiences dealing with multiple REB reviews of minimal-risk research in Canada highlights the complexity of multisite research, even when the research involves minimal risk. Documents submitted for REB approval varied across sites, as did the type of review (exempt, expedited, or full). For the 22 applications that were submitted for REB review, we encountered over 150 requests for clarification, changes, or additional documents. We also encountered significant practical and process challenges in securing the collaboration of multiple local PIs, as well as variation in time between the submission of the REB package to local PIs and REB approval. Four REBs approved a study more than 100 days after we submitted the application to the local PI, including one approval that came 500 days after the application was submitted to the PI.
Our findings have important limitations. We are reporting our experience retrospectively, and we encountered some challenges in obtaining from REBs information regarding our studies (e.g., official dates that REB application material was received). The submissions were made across a span of almost two years. It is also difficult to tease out why some delays occurred in approval (e.g., an REB approval can be held up by an REB, but also by a local PI who does not submit the application in due time to the REB). In our case, there was no financial or academic incentive for local PIs to participate in the studies. Also, the challenges we encountered (or that other researchers encounter) could depend on the nature of our research projects (minimal risk in our case), our study materials, and the Canadian regulatory and REB contexts.
Despite the limitations of our study, we believe that our experience provides important insights for discussions on the REB process in minimal-risk research, especially considering the need for evidence on the efficacy of research ethics review and governance. First, we experienced delays and variability in the REB review process, discrepancies regarding the documents required to be submitted for review, and challenges securing local PIs to participate in the studies. Our experiences and findings thus support similar reports, from the United States and the United Kingdom in particular, where researchers have stumbled across important practical challenges for REB review of multisite studies, (6) including minimal-risk studies. (7) Although we are not in a position to report exact figures regarding the cost of materials or human resources needed to support the REB application process for both of our studies, it is important to note that two trainees (one master's student and one postdoctoral fellow) committed a significant proportion of their research time to handling this process under the supervision of the PI.
Second, our experiences also raise important questions regarding the practice of multisite approval, as well as the overall approach to multisite research. The organizational and practical challenges we encountered could deter researchers from embarking on multisite research projects. The revised version of the TCPS currently under consultation (8) incorporates flexibility for "alternative review models," allowing, for example, individual REBs to recognize each other's approval (reciprocal approval) or allowing ethics approval to be delegated to a specialized or multi-institutional REB. There have been a few international experiences of multi-institutional systems for REB review. For example, in Australia, the National Statement on Ethical Conduct in Human Research states that for multisite reciprocal approval, "Wherever more than one institution has a responsibility to ensure that a human research project is subject to ethical review, each institution has the further responsibility to adopt a review process that eliminates any unnecessary duplication of ethical review." (9) In the United Kingdom, regional multicenter research ethics committees (MRECs) were created by the National Health Service. (10) Some Canadian multisite systems also exist and show encouraging signs of success. (11) However, the revised TCPS states that each REB "remains responsible for the ethical acceptability of research undertaken within its jurisdiction or under its auspices, regardless of the model adopted for multijurisdictional review of any given research project." (12) Therefore, even though the revised TCPS proposes that developing alternative models constitutes a shared responsibility of different stakeholders, it urges researchers themselves to "consider alternative review models at the planning and design stage of their research, and they should consult with their REB to facilitate the selection and coordination of the appropriate review model." (13) One of the underlying issues with this proposed piecemeal approach to ethics review and the development of alternative models is that the onus falls largely on individual researchers and institutions to identify and develop alternative models of review. It is unrealistic, though, to expect individual researchers and institutions--or even research groups and research coalitions--to dedicate the energy necessary to consolidate multisite ethics review for their studies.
Some of the challenges we encountered with multisite, minimal-risk research might be more pronounced when traditional interventional studies are involved. Regardless, our experiences and those of others who have conducted multisite studies reflect the need for ethics review systems14 that facilitate research while avoiding some of the debatable discrepancies in outcomes of multiple REB reviews and the complexity of a multiple review process. Practices for ethics review and local site collaborations impact any country's ability to develop innovative research and health care, and thus, they deserve more consideration than they currently receive.
We would like to thank Nicole Palmour for feedback on this manuscript, as well as Ghislaine Mathieu, Bruce Pike, Julien Doyon, Mary Pat MacAndrews, and Abbas Sadikot. We extend our thanks to all our local PIs who have made this research possible. This work is supported by grants from the Canadian Institutes of Health Research (States of Mind Network, New Investigator Award, and
Ethics Seed Grant; Eric Racine), the Social Sciences and Humanities Research Council (Emily Bell), and the Fonds de la recherche en sante du Quebec (FRSQ) (Eric Racine). We want to thank the reviewers for insightful and constructive comments on our manuscript.
Both research projects reported in this paper were reviewed and approved by multiple REBs.
(1.) Greene SM, Geiger AM. A review finds that multicenter studies face substantial challenges but strategies exist to achieve institutional review board approval. Journal of Clinical Epidemiology 2006;59:784-790.
(2.) Hebert P, Saginur R. Research ethics review: Do it once and do it well. Canadian Medical Association Journal 2009;180:597-598.
(3.) Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Ottawa, ON, Canada: Public Works and Public Services Canada, 1998, sec. 1.1.
(4.) See ref. 3, Tri-Council Policy Statement 1998, sec. 1.11.
(5.) Interagency Advisory Panel of Research Ethics. Draft 2nd Edition of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. Ottawa, ON, Canada, 2008.
(6.) See ref. 1, Greene and Geiger 2006.
(7.) Ah-See KW, MacKenzie J, Thakker NS, et al. Local research ethics committee approval for a national study in Scotland. Journal of the Royal College of Surgeons of Edinburgh 1998;43:303-305; Hirshon JM, Krugman SD, Wittin MD, et al. Variability in institutional review board assessment of minimal-risk research. Academic Emergency Medicine 2002;9:1417-1420; Dziak K, Anderson R, Sevik MA, et al. Variations among institutional review board reviews in a multisite health services research study. Health Services Research 2005;40:279-290; Green LA, Lowery JC, Kowalski CP, et al. Impact of institutional review board practice variation on observational health services research. Health Services Research 2006;41:214-230; Greene SM, Geiger AM, Harris EL, et al. Impact of IRB requirements on a multicenter survey of prophylactic mastectomy outcomes. Annals of Epidemiology 2006;16:275-278; Vick CC, Finan KR, Kiefe C, et al. Variation in institutional review processes for a multisite observational study. American Journal of Surgery 2005;190:805-809.
(8.) See ref. 5, Interagency Advisory Panel of Research Ethics 2008, 82-85.
(9.) National Health and Medical Research Council, Australian Research Council, Australian Vice-Chancellors' Committee. National Statement on Ethical Conduct in Human Research. Canberra, Australia: National Health and Medical Research Council, 2007, sec. 5.3.1 p. 87.
(10.) Koski G, Aungst J, Kupersmith J, et al. Cooperative research ethics review boards: A win-win solution? IRB: Ethics & Human Research 2005;27(3):1-7.
(11.) Enzle ME, Schmaltz R. Ethics review of multi-centre clinical trials in Canada. Health Law Review 2005;13:51-57; Unite de l'ethique, Direction generale adjointe de l'evaluation, de la recherche et de l'innovation, Ministere de la sante et des services sociaux. Mecanisme entourant l'examen ethique et le suivi continu des projets multicentriques, Gouvernement du Quebec, QC, 2008.
(12.) See ref. 5, Interagency Advisory Panel of Research Ethics 2008, p. 83.
(13.) See ref. 5, Interagency Advisory Panel of Research Ethics 2008, p. 84-85.
(14.) See ref. 2, Hebert and Saginur 2009.
Eric Racine, Emily Bell, and Constance Deslauriers, "Canadian Research Ethics Boards and Multisite Research: Experiences from Two Minimal-Risk Studies," IRB: Ethics & Human Research 32, no. 3: 12-18.
* Eric Racine, PhD, is Director of the Neuroethics Research Unit and Assistant Research Professor at the Institut de recherches cliniques de Montreal (IRCM), the Departments of Medicine and Social and Preventive Medicine, University of Montreal, and the Departments of Neurology and Neurosurgery and the Biomedical Ethics Unit, McGill University, Montreal, QC, Canada; Emily Bell, PhD, is Postdoctoral Fellow at the Neuroethics Research Unit, Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada; and Constance Deslauriers is a Master's degree student at the Neuroethics Research Unit, Institut de recherches cliniques de Montreal (IRCM), Montreal, QC, Canada.
Table 1. Overview of Two Canadian Multisite, Minimal-Risk Research Studies Study A Study B Title Identifying practices A multisite and challenges for REB qualitative study of review of advanced ethical and social neuroimaging in Canada issues in functional neurosurgery using neurostimulation Rationale There are emerging Recent studies have ethical challenges expanded the research related to research use of ethics but limited neurostimulation understanding about (e.g., treatment- how Canadian resistant depression, neuroimaging obsessive-compulsive researchers and REBs disorder), yet there are dealing with them. are few if any empirical studies identifying and characterizing the ethical and social landscape of both current and emerging neurostimulation practices. Goals and 1) Identify the 1) Identify and objectives practices of REB characterize current approval of advanced ethical and social neuroimaging research issues in the and the language used application of to describe risks and neurostimulation. ethical issues in REB approved neuroimaging 2) Identify and protocols. characterize emerging ethical and social 2) Examine the issues in the challenges of REB extension of review of advanced neurostimulation to neuroimaging research psychiatric disorders. as well as current solutions based on the 3) Identify potential perspective of solutions to address neuroimagers and REBs. current and emerging issues in the 3) Recommend application and strategies to address extension of gaps in current neurostimulation. practices and promote the sharing of promising solutions for the review of advanced neuroimaging research. Methods Online questionnaire Paper and pencil questionnaire Qualitative content analysis of onsite Qualitative content interview or phone analysis of onsite interview interview or phone interview Qualitative content analysis of researchers' two most recent approved consent forms Recruited Neuroimaging Health care providers populations researchers and REB involved in the care chairs of neurostimulation patients Table 2. Details of REB Review for Two Canadian Multisite, Minimal-Risk Research Projects Site Type of review Number of days Number of days submission for approval for approval (after (after submission to submission by local PI) local PI to REB) (a) Study A. REB review of a study identifying practices for REB review of advanced neuroimaging in Canada A1 Full N/A 39 A2 Expedited 25 6 A3 Full 86 82 A4 Expedited 19 18 A5 Exempt N/A 19 A6 Expedited 11 7 A7 Expedited 546 489 A8 Expedited 18 16 A9 Expedited N/A 4 A10 Expedited 22 22 A11 Expedited 4 NO A12 Expedited 108 NO A13 Expedited 18 NO A14 Expedited 158 NO A15 Expedited 27 26 Study B. REB review of a study of ethical and social issues in functional neurosurgery using neurostimulation B1 Full N/A 14 B2 Expedited NO 3 B3 Expedited 143 NO B4 Expedited 80 NO B5 Expedited 27 8 B6 Expedited 67 63 B7 Expedited 30 NO Site Documents required for REB review (b) submission Study A. REB review of a study identifying practices for REB review of advanced neuroimaging in Canada A1 EAA; P; ST; RA; CF; OB; CV A2 P; ST; RA; REBs (1); CF A3 EAA; ST; RA; REBs (3); CF; PL; LS A4 P; ST; RA; REBs (2); CF A5 P; RA; ST A6 P; ST; RA; REBs (4); CF; OB A7 EAA; P; ST; CF; OB; DT A8 EAA; P; ST; RA; REBs (6); CF; OB; CV A9 P; ST; RA; REBs (7); OB A10 EAA; P; ST; RA; REBs (7); CF; OB; CV; PL A11 EAA; P; ST; RA; REBs (7); CF; OB A12 EAA; P; ST; RA; REBs (9); CF; OB; LS A13 EAA; P; ST; RA; REBs (8); CF; OB A14 EAA; P; ST; RA; REBs (9); CF; LS; CHE A15 EAA; P; ST; REBs (12); CF; OB; TCPS Study B. REB review of a study of ethical and social issues in functional neurosurgery using neurostimulation B1 EAA; P; ST; RA; CF; OB; CV (3) B2 EAA; P; ST; RA; CF B3 EAA; P; ST; RA; REBs (2); CF; OB B4 EAA; P; ST; RA; REBs (2); CF; LS (2); CHE B5 EAA; P; ST; RA; REBs (4); CF; INST (1); TCPS B6 EAA; P; ST; RA; REBs (4); CF; OB; CV; INST (2) B7 EAA; P; ST; RA; REBs (4); CF; OB EAA--ethics approval application RA--recruitment advertising CV--curriculum vitae PL--presentation letter INST--institutional approval P--research protocol REBs--previous REB approvals CF--consent form LS--letter of support TCPS--Tri-Council Policy Statement Certification ST--study tools (questionnaire and/or interview grid) OB--operating budget DT--departmental approval CHE--checklist of application (a) NO: The exact date that REB application was received was not obtainable from this local REB. (b) Number in parentheses indicates number of previous REB approvals submitted. Note: A "letter of support" was built into several EAAs that required departmental signatures (n = 7 for study A; n = 4 for study B) instead of a separate letter of support. The following were submissions to the same sites (A1/B1; A2/B2; A10/B6; A11/B7; A12/B3; A14/B4; A15/B5). Table 3. Queries for Clarifications and Changes Presented by REBs for Two Canadian Multisite, Minimal-Risk Research Projects Study A Study B (Number of (Number of clarifications clarifications and changes) and changes) 1. Consent form (subtotals) 45 17 Site Specifications Change in format (e.g., 11 5 local site letterhead, header/footer ethics approval numbers, version changes, PI names and information) Provide local PI name to 5 1 contact information in case of emergency Provide site-specific 4 1 research office contact information Data Storage and Privacy Clarify data storage 9 1 procedures (change in wording) Clarify means of data 3 1 storage at principal site Clarify how long 2 2 audiotapes will be stored Language Changes Clarify sentences 7 3 (typographical error or change in wording) Change site standard 2 1 wording that did not apply to the studies Change wording of section 1 1 on new information Change wording of section 1 1 on right to privacy 2. Ethics approval 49 10 application and research protocol (subtotals) Clarify the exclusion 3 0 criteria Clarify the standard of 0 1 care for this patient population Data Storage and Privacy Clarify total length of 9 0 data storage (from five to 15 years) Clarify which members of 6 1 the team will be onsite to carry out the study Provide names of members 5 0 or research personnel who will have access to data Clarify means of data 4 0 destruction Clarify where the data is 3 0 being stored (another site from where it is collected) Clarify means of data 0 1 storage (on a laptop) Researcher's Qualifications Provide all collaborator 3 0 and co-PI's signatures for ethics approval Provide contact 2 1 information for all co-PIs Provide CVs for all 2 1 co-PIs Provide signatures on EAA 1 2 from all co-PIs Obtain local PI signature 1 0 for confidentiality agreement Obtain local PI signature 0 1 for agreement to access of personal health information Funding Populations Provide proof of funding 9 1 agreement in addition to operating grant information Require to contact 1 1 research services office about whether a research services file is needed 3. Recruitment and 10 0 advertisement (subtotals) Obtain institutional 4 0 approval on poster Provide first contact 3 0 script (e-mail or phone) Provide local PI info on 2 0 poster Change the title of study 1 0 4. Survey, questionnaire, 19 5 and interview grid (subtotals) Change in format (e.g., 12 5 local site letterhead, header/footer ethics approval numbers, version changes, PI names and information) on study Clarify French and 2 0 English translation (asked for change in wording) Change order of questions 2 0 in online survey Change in survey methods 2 0 (no use of the Survey Monkey software) Change in survey content 1 0 (consent being separated from online survey) TOTALS 123 32
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