What went wrong: A reckoning of Canada’s contributions to evidence-based medicine through clinical trials during the COVID-19 pandemic

Rarely in history have the world’s scientific efforts been so singularly focused on a shared problem as during the coronavirus disease 2019 (COVID-19) pandemic. Since early 2020, scientists around the world have worked tirelessly to find solutions to contain, prevent, diagnose, and treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of generating knowledge—from creating scalable diagnostics, to testing repurposed and novel therapies, to the generation of safe and effective vaccines—has been astounding.

Although all nations were affected by COVID-19, not all of them were equipped with the resources and the expertise to generate high-quality clinical trial data to guide practice during the pandemic. Canada, a wealthy nation with universal health care and world-class investigators should, on the surface, have been poised to lead the world in practice-changing randomized clinical trials. Unfortunately, despite important efforts, it fell short of the mark: Canadian trialists have been involved in only a handful of substantial projects, with the majority of the advancements being driven by scientists elsewhere. Despite substantial investments from the Canadian government, this mainly occurred as a result of several logistical administrative barriers. Here we outline some of the challenges encountered in conducting research in the Canadian context, which could be addressed and improved on as we enter the inevitable next waves of the pandemic.

How Other Countries Succeeded

The gold standard in terms of the rapid generation of high-quality clinical trial evidence during the pandemic is the United Kingdom and its crown jewel, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial. Initially funded for £2.1 million, the RECOVERY platform has produced critical evidence for identified or validated life-saving therapies such as dexamethasone (1), tocilizumab (2), and monoclonal antibodies among select hospitalized patients (3), and it has definitively debunked unhelpful and potential harmful interventions such as hydroxychloroquine (4), lopinavir–ritonavir (5), convalescent plasma (6), aspirin (7), azithromycin (8), and colchicine (9). The speed with which the RECOVERY trial was designed, approved by regulators, and initiated was remarkable, with the first patient recruited 9 days after the protocol was finalized; within 15 days, more than 1,000 patients had been enrolled (10). In less than 100 days, RECOVERY delivered its first landmark result: proof of the life-saving benefits of dexamethasone (1). As of the end of August 2021, RECOVERY had recruited more than 40,000 patients across 177 hospitals, representing approximately 10% of all COVID-19 admissions in the United Kingdom (10).

How Canada Fared

By contrast, the major national inpatient trial in Canada, the Canadian Arm of the Solidarity Trial (CATCO), has at the time of writing received approximately $8 million in Canadian Institutes of Health Research operating grants to participate in the World Health Organization’s Solidarity platform. This platform had one interim report in October 2020, in which Canadian data were pooled with the data from Europe (11). This report provided additional evidence against hydroxychloroquine and lopinavir–ritonavir, as well as the first large look at interferon-1-beta and an independent unfavourable analysis of remdesivir. Overall, the CATCO has recruited approximately 1,500 patients from approximately 60 Canadian sites. Since the October 2020 report, testing of new candidate drugs has been slow. Although Canada has contributed patient recruitment to a several outpatient trials (12, 13), others were halted because of failure to recruit, including promising studies of inhaled ciclesonide (ClinicalTrials.gov identifier NCT04435795) and oral fluvoxamine (ClinicalTrials.gov identifier NCT04668950). One trial, Colchicine Coronavirus SARS-CoV2, that looked at colchicine use among outpatients with COVID-19 was funded to the tune of approximately $14 million only to be stopped early because of recruitment and staffing challenges, ultimately delivering underpowered and inconclusive results (14). Another trial (ClinicalTrials.gov identifier NCT04483635) received $4 million to study vitamin D administration to prevent COVID-19 but was terminated after recruiting just 34 individuals out of a planned sample size of 2,414 health care workers.

To be sure, some Canadian-led international trials contributed important knowledge. Notable examples include the Antithrombotic Therapy to Ameliorate Complications of COVID-19 trial, led by the Universities of Manitoba and Toronto, which showed the benefit of therapeutic anticoagulation among ward patients with COVID-19 (15) and potential harm among those in the intensive care unit (16), and the Together Trial, which is evaluating outpatient therapies and is led by a leadership team in Canada (17) but actually recruits patients in Brazil. However, these successes have been the exception and not the rule. There are few examples of large Canadian-led studies that largely took place in Canada (14).

Why Canada Failed

Canadian contributions to clinical trial evidence during the pandemic have been limited for several reasons. The first relates to the slow and arduous pace of obtaining funding and executing legal agreements among funders, sponsors, and the many institutions that might participate in a multicentre trial. There are few funding agencies, and the application process, review, and then distribution of awards is mired in bureaucracy and occurs at a glacial pace. For sites to participate in multicentre trials, contracts are required to allay concerns about financial and legal liability. These often take many weeks or months to be executed, even when expedited during a pandemic. In some cases, by the time funding is awarded and contracts are in place, the questions have been answered by researchers from other countries or the landscape has changed, rendering the study infeasible. For example, the Canadian Immunization Research Network was awarded $4.8 million for a randomized controlled trial of heterologous vaccine schedules, but the funding was tied up in red tape so long that by the time the trial could begin, heterologous vaccination was already standard practice in many provinces.

Second, structured coordination among provinces, cities, and research institutes is lacking. For example, early in the pandemic, multiple Canadian groups simultaneously embarked on small, ultimately underpowered trials of hydroxychloroquine. In addition, the provincial coordination of health care has resulted in the lack of a mechanism to easily and safely share data or ethics oversight. The need for independent ethics review by every university and hospital and the refusal to defer review to a delegated central research ethics board results in replication of work and inefficiencies.

The Next Pandemic

So what can be done to better position Canada to contribute in the next pandemic? First, an overhaul is required to allow the integration of clinical trials into routine care. Second, Canada needs a federal body able to sponsor and coordinate clinical research, similar to the US National Institutes of Health. Such a body would enable the coordination of a national network of investigations and research teams with the ability to rapidly deploy prioritized research. Ideally, such an administrative body would be able to issue centralized ethics approval and legal and financial protection across sites. Likely this needs to occur at the federal level with provincial buy-in to allow interprovincial research studies. Third, investment in clinical research—particularly network-based clinical trials—needs to increase more broadly, even between pandemics, so that the necessary personnel and research infrastructure are in place and can be rapidly mobilized when needed. Ultimately, a thorough post-mortem examination will be needed by those with the power to enact lasting and meaningful change so that Canadian clinician-scientists can play a more supportive role in the next pandemic.

Ethics Approval:

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Informed Consent:

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Registry and the Registration No. of the Study/Trial:

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Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

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