A call for a streamlined ethics review process for multijurisdictional, child health research studies

Abstract

To be time and resource efficient in neonatal research and to answer clinically relevant questions with validity and generalizability, large numbers of infants from multiple hospitals need to be included. Multijurisdictional research in Canada is currently fraught with research ethics review process hurdles that lead to delays, administrative costs, and possibly termination of projects. We describe our experience applying for ethics review to 13 sites in 7 provinces for a project comparing two standard of care therapies for preterm born infants with respiratory distress syndrome. We welcome the current opportunity created by the Institute of Human Development Child and Youth Health and the Institute for Genetics, to collaboratively identify practical solutions that would benefit Canadian researchers, Research Ethics Boards, and children and families.

Infants born ‘very preterm’, i.e., less than 32 weeks gestational age, represent about 30% of all admissions in Canadian Neonatal Intensive Care Units (NICUs). In 2017, 3,490 such infants were admitted to one of 33 NICUs participating in the Canadian Neonatal Network (CNN), which is an Research Ethics Board (REB)-approved database, which collects data on clinical outcomes and health resources use.

Often, more than a single ‘accepted or usual’ treatment is available for the same clinical condition with varying practices between NICUs. To answer questions on what treatments are ‘best practice’ in a valid and generalizable way, inclusion of large numbers of patients is typically needed. To be time- and resource-efficient, most of the NICUs across the country would need to take part in comparative safety and cost-effectiveness studies, especially if they involve very preterm infants. Even when ‘accepted or usual’ treatments are compared in such studies, the project must be approved by each local REB.

We recently submitted a project to 13 REBs in 7 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, New-Brunswick and Nova-Scotia), and experienced unexpected hurdles and delays. Using real-world data, the project’s aim is to compare the cost-effectiveness of two animal-derived surfactant preparations used for the treatment of respiratory distress syndrome. Both surfactants received marketing authorization from Health Canada for this indication and are currently used in Canadian NICUs, although one (surfactant A) has been on the Canadian market for over 20 years while the other (surfactant B), used world-wide for more than 20 years, has become available in Canada since 2017.

Before proceeding with the study, we established that there was ‘equipoise’ amongst Canadian clinicians with regards to the comparative effectiveness and cost-effectiveness of both surfactants. While both are safe and effective products, there is very limited evidence comparing surfactants A and B—not enough to make a rational choice between them (1). We do know that Surfactant B is more expensive than Surfactant A, but does it improve lung health, and does it lead to reduced healthcare system expenses during the admission, as suggested by previous research comparing it to surfactants other than Surfactant A? Our study design delineated that each participating NICUs would provide solely surfactant A to their patients for 6 months during a calendar year and surfactant B for the other 6 months. Data on relevant clinical outcomes and costs to the health care system will be compared at the end of this timeframe, using data that CNN already has approval to collect at each site for benchmarking and quality improvement purposes.

Appraisals of the project from the various REBs were extremely variable with one REB requesting the project follow the rules of a Division 5 regulated trial including extensive monitoring as per Good Clinical Practice, while others assessed the project as meeting the ‘less than minimal risk’ criteria and approved it with a waiver of parental consent. Some REBs viewed the project as quality-improvement, indicating that it could be conducted without REB approval. The whole process took 1 year of writing letters, calling local REB officials, waiting for replies, and providing further explanations.

Such disparities in REB perspective with polar opposite assessments are difficult to understand. They jeopardize large-scale multisite projects, particularly in postmarketed drugs that are already used in daily practice, where establishing comparative effectiveness and safety in the real-world and establishing cost-effectiveness in a publicly funded health care system are critically needed. These delays and discrepancies discourage well-meaning clinician-researchers who may forego participation, which denies patients from taking part in research, limiting the evidence available to inform clinicians’ and health care administrators’ decisions, and, ultimately, denying children from getting the ‘best’ treatment.

Our struggles in this ‘muddled Canadian landscape’ with multisite inter-provincial research are not unique. Paediatric drug trials, which are crucially needed to establish safe prescribing for children and infants, suffer the same struggles, with markedly different requirements to satisfy each local REB (2). While we experienced disparity in the assessment of level of ‘risk of participation’, Canadian researchers, trying to establish a national perinatal database, report disparities between REBs involved the application process itself, privacy concerns and assessment of local resources availability to perform the research (3). Similarly, paediatric rheumatology researchers report that they experienced issues with the content of the consent form and nonuniformity of the application for REB review (4). The TriCouncil Policy Statement (TCPS 2018), Canada’s guiding human research ethics policy, sets out options, procedures, and considerations for the ethics review of multijurisdictional research either entirely within Canada, or in Canada and other countries. And yet, despite this guidance, streamlined ethics review across Canada’s federated jurisdictions remains abysmal.

REBs need to fulfill their mandate with due diligence to protect the rights of study participants. There must however be a way to reduce unwarranted variability in reviews and decisions and be more efficient. In fact, there have been a number of editorial commentaries, and ‘calls for action’ on this subject by individuals prominent in the research ethics community in Canada (5,6). In these, proposed solutions include the adoption of a common REB application form for all REBs, consideration for a national, specialty specific REB (4), and a streamlined local process, after one national REB review (5). More recently, members of the Canadian Clinical Trials Coordinating Centre REB Accreditation Working Group suggest to build on already existing provincial initiatives with the creation of a national leadership body (6).

In countries such as the UK, France, and Australia, a single Research Ethics Committee review is required for nation-wide clinical trials. In the USA, National Institutes of Health-funded multisite domestic studies are expected to use a single REB as of January 2018. In Canada, over the last several years, efforts have been made by three provinces (Labrador and Newfoundland, Quebec, and Ontario), to harmonize processes, reduce time, and effort, and advance a streamlined research ethics review system within their jurisdictions. An editorial report reduced times to obtain REB approval with Clinical Trials Ontario (CTO) (7). CTO is still not commonly used in Paediatrics due to the need for paediatric representation on the REB of Record for studies considered above-minimal risk, which, until recently, meant that only the Hospital for Sick Children REB would qualify. Our project was not submitted to CTO, as the REB Chair of the principal investigator’s institution assessed the project as quality improvement. Provincial initiatives are an excellent step towards harmonization but will not solve issues for research that needs to take place nationally, which is now almost the norm in our field.

A common message from previous advocates, that we reiterate, is that national leadership is required to overhaul our current ethics review process for national multicentre studies. Such leadership needs to bring REBs and researchers together, determine real and perceived barriers, and then re-examine processes to streamline the process and build on existing initiatives, thus reducing the workload on REBs and researchers and bringing the research to the patients in a timely fashion. Issues of process (application form content) and of research ethics review per se (e.g., level of risk and burden assessment, consent form content) need to be addressed to improve the experience and reduce delays.

We propose the development of a ‘one-stop shop’ where all multicentre child health research studies (not exclusively clinical trials) are reviewed by one REB with all the needed qualifications. This could be achieved with the creation of a collaborative platform using the CTO model to streamline the review process. This would ultimately, minding all legislative difference within provinces, achieve a single ethics review for multijurisdictional research studies. This new infrastructure would provide educational material to both researchers and REB members to foster standardized and consistent application and review practices.

CONCLUSION

In November 2019, the Canadian Institute for Health Research Institute of Human Development, Child and Youth Health (CIHR-IHDCYH) and the CIHR Institute of Genetics (CIHR-IG) are launching a funding opportunity for a multidisciplinary team to develop a streamlined approach for research ethics review and build a platform with a single point of contact for child health researchers. This represents the first serious national initiative to try to address harmonization and streamlining of ethics review and creates hope for young patients and families who could greatly benefit from inclusion in highly needed, well designed, ethical research.

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.